Neuromodulation of Ganglia

ABSTRACT

Modulation of neural activity of a ganglion, by applying a signal to a sympathetic nerve adjacent to the ganglion, results in preferential reduction of sympathetic signals to an effector, thereby providing ways of treating and preventing conditions associated with exacerbated sympatho-excitation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/771,441 filed Jun. 10, 2020, which is a U.S. National Stageapplication under 35 U.S.C. § 371 of International ApplicationPCT/GB2018/053599 (published as WO 2019/116029 A1) filed Dec. 11, 2018,which claims the benefit of priority to U.S. provisional Application No.62/597,256 filed Dec. 11, 2017. Each of these prior applications arehereby incorporated by reference in their entirety.

TECHNICAL FIELD

This invention relates to neuromodulation of ganglia to achievetherapeutic effects. More specifically, the invention relates to medicaldevices and systems that modulate the neural activity of ganglia toachieve therapeutic effects.

BACKGROUND ART

A ganglion is made of cell bodies of afferent and efferent nerves.Ganglia often interconnect with other ganglia to form a complex systemof ganglia. Ganglia provide relay points and intermediary connectionsbetween different neurological structures in the body, such as theperipheral and central nervous systems.

Therapeutic treatments involving targeting the ganglia have beeninvestigated. For example, attempts to treat cardiac dysfunctions suchas ventricular arrhythmias include targeting ganglia within the cardiacsympathetic nervous system by electrical stimulation or transection,which resulted in modulation of autonomic imbalances and reducedarrhythmias. One surgical approach to treat ventricular arrhythmiasinvolves the resection of stellate ganglion [1,2,3,4]. Electricalstimulation of cardiac-related nerves with the aim to treat cardiacdisorders has been reported, e.g. in references [5] and [6]. Highsympathetic or neural tone can be causative or result in manypathologies, and treatment paradigm might involve reducing the high tonein the ganglia and post ganglionic nerves thereof. Techniques toaccomplish this involve conduction block of nerves.

However, treatments that are currently under research typically requirea high charge density per phase to produce a therapeutic effect. This isnot ideal for clinical applications because of the collateral damagethat may be caused by the high charge density per phase applied to thenerve, especially when applied in the long term. Moreover, the highenergy requirement because of the high charge density per phase limitsbattery life of an implant for electrical stimulation. Also, the need toapply a high charge density per phase limits the design options for theneural interfacing elements.

The invention therefore aims to provide further and improved ways ofmodulating ganglia to achieve therapeutic effects. In particular, theinvention aims to provide further and improved ways of treating andpreventing conditions where the pathology is driven by exacerbatedsympatho-excitation, e.g. cardiac dysfunction, and metabolic disorderswhich involve impaired glucose control, such as T2D.

SUMMARY OF THE INVENTION

The invention relates to restoring the body's homeostasis by modulatingafferent-mediated decreases in central sympathetic drive. This can beachieved by modulating the neural activity of a ganglion which leads topreferential reduction of efferent sympathetic signals to its effector.In particular, the invention involves applying electrical signals havinga charge density per phase below a predetermined threshold to asympathetic nerve at a site adjacent to a ganglion to incite actionpotentials that preferentially propagate away from an effector, towardsthe ganglion. This preferentially leads to a change in the electricalproperties of the ganglionic cell bodies adjacent to the signalapplication site, e.g. the ganglion which the action potentials (ascreated by the signal) travel towards, resulting in reduced efferentsympathetic signals to the effector. The change in electrical propertiesof the ganglionic cell bodies may involve re-organization to silence theexcitatory cell bodies and bring about homeostasis in the ganglioniccell bodies. One of the processes this might result in would beincreasing the refractoriness of the ganglionic cell bodies that wouldmake them resistant to incoming volleys from CNS.

Thus, the invention provides a system for reversibly modulating theneural activity of a sympathetic nerve. The system comprises at leasttwo neural interfacing elements suitable for placement on or around thenerve adjacent to a ganglion, wherein the ganglion transmits sympatheticsignals between the ganglion and an effector, and at least one voltageor current source configured to generate at least one electrical signalto be applied to the nerve, via the at least two neural interfacingelements, to modulate the neural activity of the nerve to reducesympatho-excitation in the effector. The at least two neural interfacingelements are configured such that the electrical signal incites actionpotentials in the nerve that propagate away from the effector, towardsthe ganglion, and the charge density per phase applied to the nerve bythe electrical signal is below a predetermined threshold, thepredetermined threshold defined as the minimum charge density per phaserequired to produce a response associated with sympatho-excitation inthe effector by modulating the neural activity of the sympathetic nerve.

The application of an electrical signal having a charge density perphase below the predetermined threshold to a sympathetic nerve at a siteadjacent to a ganglion, to incite action potentials that preferentiallypropagate away from the effector, towards the ganglion (i.e. in theafferent direction) is advantageous because the signal is sufficient tomodulate the electrical properties of the nerve causing a change inelectrical properties of the ganglionic cell bodies adjacent to thesignal application site, such as ganglionic refractoriness, but notsufficient to produce responses that are associated withsympatho-excitation in the effector. Furthermore, the body's regulatorycontrol mechanisms are tightly regulated, and so if the control systemsare pushed in one way by exogenous inputs, e.g. by applying anelectrical signal having a high charge density per phase (above thepredetermined threshold) as disclosed in the prior art, the endogenousreflexes would push back to maintain homeostasis, which would result inreduced efficacy of processing in the ganglia.

The invention is based on literature suggesting that altered neuralsignaling in nerve structures that contain ganglia, e.g. the sympatheticchain or the GSN, may be associated with an imbalance of sympatho-vagalsignaling. For example, cardiac pathology is suggested to be associatedwith altered neural signaling in cardiac ganglia resulting in animbalance of sympatho-vagal signaling. This leads to deviations inproperties of intracardiac ganglia. Use of neuromodulatory approaches atthe sympathetic chain has been shown to result in improvements incardiac function [7]. It has been reported that unilateral stimulationof the stellate ganglion and the ansae subclavia, respectively, wereable to influence the electrophysiological properties of the heart[8,9].

The invention is also supported by a report showing that refractorinessin a nerve in mice can be caused by low frequency stimulation (1 Hz)[10]. It was found that the refractoriness may be caused by intensifiedinternalization of sodium channels leading to irreversible decline ofthe compound action potential amplitude.

It has also been demonstrated in other nerve structures that lowfrequency stimulation of these nerve structures led to depression inpostganglionic transmission, contributing to the reduction insympathetic tone. These nerve structures are similar in that theycontain ganglia, convey both afferent and efferent sympathetic signals,and the signal transmissions are complex involving extensive ganglionicprocessing. For example, the inventors found that directionalstimulation of a nerve structure similar to the sympathetic chainganglia led to refractoriness in neural signaling and impacted onbaseline physiology [11]. It was also found that low frequencystimulation of the hypogastric nerves in cats inhibited discharge fromthe pelvic ganglia, thereby contributing to sympathetic depression ofbladder activity [12].

Reference [13] shows that bipolar cervical vagus nerve stimulationreflected a dynamic interaction between afferent mediated decreases incentral parasympathetic drive and suppressive effects evoked bydirectional stimulation of parasympathetic efferent axons to the heart.In particular, Reference [13] shows that different cardiac responseswere evoked by changing bipolar electrode orientation (i.e. either anodecephalad to cathode (“cardiac” configuration) which incites actionpotentials which propagate preferentially towards the heart; or cathodecephalad to anode (“epilepsy” configuration) which incites actionpotentials towards the brain.

The invention also provides a method for reversibly modulating theneural activity of a sympathetic nerve, comprising: placing at least twoneural interfacing elements on or around the nerve adjacent to aganglion, wherein the ganglion transmits sympathetic signals between theganglion and an effector; and applying, by at least one voltage orcurrent source, at least one electrical signal to the nerve, via the atleast two neural interfacing elements, to modulate the neural activityof the nerve to reduce sympatho-excitation in the effector, wherein theat least two neural interfacing elements are configured such that theelectrical signal incites action potentials in the nerve which propagateaway from the effector, towards the ganglion, wherein the charge densityper phase applied to the nerve by the electrical signal is below apredetermined threshold, the predetermined threshold defined as theminimum charge density per phase required to produce a responseassociated with sympatho-excitation in the effector by modulating theneural activity of the sympathetic nerve.

The invention also provides charged particles for use in a method oftreating or preventing a condition where the pathology is driven byexacerbated sympatho-excitation, wherein the charged particles causereversible depolarization and hyperpolarization of the nerve membrane ofa sympathetic nerve adjacent to a ganglion, such that action potentialsthat propagate along the nerve toward the ganglion are created de novoin the modified nerve, wherein the ganglion transmits sympatheticsignals between the ganglion and an effector, wherein the neuralactivity of the modified nerve between the ganglion and the effector ismodulated to reduce sympatho-excitation in the effector, wherein thecharge density per phase of the charged particles is below apredetermined threshold, the predetermined threshold defined as theminimum charge density per phase required to produce a responseassociated with sympatho-excitation in the effector by modulating theneural activity of a nerve.

The invention also provides a modified sympathetic nerve wherein atleast two neural interfacing elements of a system of the invention areattached to the nerve adjacent to a ganglion, wherein the at least twoneural interfacing elements are in signaling contact with the modifiednerve and so the modified nerve can be distinguished from the nerve inits natural state, and wherein the nerve is located in a patient whosuffers from a condition where the pathology is driven by exacerbatedsympatho-excitation.

The invention also provides a modified sympathetic nerve having a nervemembrane that is reversibly depolarized and hyperpolarized by chargedparticles, the depolarization and hyperpolarization being induced byapplying an electrical signal at the nerve adjacent to a ganglion,wherein the ganglion transmits sympathetic signals between the ganglionand an effector, such that action potentials that propagate along thenerve toward the ganglion are created de novo in the modified nerve,wherein the neural activity of the modified nerve between the ganglionand the effector is modulated to reduce sympatho-excitation in theeffector, wherein the charge density per phase of the charged particlesis below a predetermined threshold, predetermined threshold defined asthe minimum charge density per phase required to produce a responseassociated with sympatho-excitation in the effector.

The invention also provides a modified sympathetic nerve obtainable byreversibly modulating neural activity of the modified nerve according toa method of the invention.

The invention also provides a modified ganglion adjacent a modifiedsympathetic nerve of the invention, wherein the modified ganglion has areduced capacity to transmit sympathetic signals to the effector.

The invention also provides a method of reversibly modulating neuralactivity in a sympathetic nerve, comprising: (i) implanting in thesubject a system of the invention; (ii) positioning the at least twoneural interfacing elements of the system at the nerve adjacent to aganglion; and optionally (iii) activating the system.

The invention also provides a method of controlling the system of theinvention, wherein the system is in signaling contact with a sympatheticnerve adjacent to a ganglion, wherein the ganglion transmits sympatheticsignals between the ganglion and an effector, the method comprising astep of sending control instructions to the system, in response to whichthe system applies a signal to the nerve at between the ganglion and theeffector, wherein the charge density per phase of the charged particlesis below a predetermined threshold, predetermined threshold defined asthe minimum charge density per phase required to produce a responseassociated with sympatho-excitation in the effector.

The invention also provides a computer-implemented method comprisingreversibly modulating the neural activity of a sympathetic nerve, themethod comprises: applying by at least one voltage or current source ofa system of the invention, at least one electrical signal to the nerveadjacent to a ganglion, via at least two neural interfacing elements, tomodulate the neural activity of the nerve to reduce sympatho-excitationin the effector, wherein the at least two neural interfacing elementsare configured such that the electrical signal incites action potentialsin the nerve which propagate away from the effector towards theganglion, wherein the charge density per phase applied to the nerve bythe electrical signal is below a predetermined threshold, thepredetermined threshold defined as the minimum charge density per phaserequired to produce a response associated with sympatho-excitation inthe effector.

The invention also provides a computer comprising a processor and anon-transitory computer readable storage medium carrying an executablecomputer program comprising code portions which when loaded and run onthe processor cause the processor to: apply, by at least one voltage orcurrent source of a system of the invention, at least one electricalsignal to the nerve adjacent to a ganglion, via at least two neuralinterfacing elements, to modulate the neural activity of the nerve toreduce sympatho-excitation from the ganglion in the effector, whereinthe at least two neural interfacing elements are configured such thatthe electrical signal incite action potentials in the nerve whichpropagate away from the effector towards the ganglion, wherein thecharge density per phase applied to the nerve by the electrical signalis below a predetermined threshold, the predetermined threshold definedas the minimum charge density per phase required to produce a responseassociated with sympatho-excitation in the effector.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram depicting the gross anatomic arrangementof the intrathoracic ganglia and associated mediastinal neuralstructures.

FIG. 2 is a schematic diagram depicting the gross anatomic arrangementof the adrenal innervation. The adrenal glands, abdominal artery, celiacganglion, suprarenal ganglion, and the posterior and anterior divisionsof the branch of the GSN supplying the adrenal gland between thesuprarenal ganglion and the adrenal gland are labelled.

FIG. 3 is a schematic diagram depicting neural interface arrangements onthe sympathetic chain.

FIG. 4 is a schematic diagram depicting neural interface arrangements onthe greater splanchnic nerve.

FIGS. 5A-5B are schematic diagrams showing some electrode configurationsfor determining the predetermined threshold. FIG. 5A shows a firstelectrode configuration. FIG. 5B shows a second electrode configuration.

FIGS. 6A, 6B, and 6C are schematic diagrams showing some electrodeconfigurations for inciting action potentials preferentially in aparticular direction. FIG. 6A shows an imbalanced surface areaconfiguration. FIG. 6B shows a recessed electrode configuration. FIG. 6Cshows an imbalanced insulation configuration.

FIGS. 7A-7B are schematic diagrams depicting neural interfacearrangements on the sympathetic chain. FIG. 7A shows a single neuralinterface on the branch between T1-T2 ganglia. FIG. 7B shows a firstneural interface on the branch between T1-T2 ganglia, and a secondneural interface on the branch between T2-T3 ganglia. C8 represents C8ganglion, T1 represents T1 ganglion, T2 represents T2 ganglion, T3represents T3 ganglion, T4 represents T4 ganglion.

FIGS. 8A-8B are schematic diagrams depicting neural interfacearrangements at the GSN branches. FIG. 8A shows a single neuralinterface at the GSN branch between the suprarenal and celiac ganglia.FIG. 8B shows a first neural interface at the GSN branch between thesuprarenal and celiac ganglia, and a second neural interface at the GSNbranch between the celiac ganglion and the foregut.

FIG. 9 is a block diagram illustrating elements of a system forperforming electrical neuromodulation in a sympathetic nerve accordingto the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Signal Application Site

The invention involves application of an electrical signal to asympathetic nerve adjacent to a ganglion. For example, the signalapplication site may be at a sympathetic nerve in the sympathetic chainor in a branch of the greater splanchnic nerve (GSN). In someembodiments, the signal application site may be at an interganglionicnerve branch, e.g. between intrathoracic ganglia in the sympatheticchain, or between the suprarenal and the celiac ganglia. In someembodiments, the signal application site may be between a ganglion andan effector, e.g. between the celiac ganglion and the foregut.

The signal application site is preferentially within 1 cm, 0.5 cm, 0.25cm, 1 mm, 500 μm, 25 μm, or 10 μm of a ganglion. Without wishing to bebound by theory, it is postulated that the effectiveness in changing theelectrical properties of the ganglionic cell bodies (such as ganglionicrefractoriness) is proportional to the distance between the signalapplication site and the ganglionic cell bodies.

The invention involves applying the electrical signal to both afferentand efferent fibers of a sympathetic nerve. For example, the signalincites action potentials, such that orthodromic action potentialstravel in the afferent fibers and/or antidromic action potentials travelin the efferent fibers.

Signal application sites that are useful with the invention arediscussed further below.

A Cardiac-Related Sympathetic Nerve

The invention aims to restore the heart's homeostasis by modulatingafferent-mediated decreases in central sympathetic drive. To causeafferent-mediated decreases in central sympathetic drive, the inventioninvolves inciting action potentials at a certain site in acardiac-related sympathetic nerve, and this causes changes in theelectrical properties of the ganglionic cell bodies adjacent to thesignal application site (such as ganglionic refractoriness), therebyresulting in reduced efferent sympathetic signals to the heart.

The signal application site may be at a cardiac-related nerve in aninterganglionic branch in the sympathetic chain. Preferably, theinterganglionic branch is between intrathoracic ganglia. Intrathoracicganglia are located within the thorax along the sympathetic chain, andthey are arranged in vertebrate animals, such as humans, as follows (indescending order from the rostral end of the spinal cord): the middlecervical ganglion, the inferior cervical ganglion (also known as the C8ganglion), the T1 ganglion, the T2 ganglion, the T3 ganglion, and the T4ganglion.

The inferior cervical ganglion is fused with the T1 ganglion to form asingle structure called the stellate ganglion in around 80% of the humanpopulation. Hence, in certain human individuals, the intrathoracicganglia are located along the sympathetic chain as follows (indescending order from the rostral end of the spinal cord): the middlecervical ganglion, the stellate ganglion, the T2 ganglion, the T3ganglion, and the T4 ganglion.

A signal application site that is useful with the invention may becaudal to the middle cervical ganglion, caudal to the inferior cervicalganglion, caudal to the stellate ganglion, caudal to the T1 ganglion,caudal to the T2 ganglion or caudal to the T3 ganglion.

The signal application site may be cranial to the T4 ganglion, cranialto the T3 ganglion, cranial to the T2 ganglion, cranial to the T1ganglion, cranial to the stellate ganglion, cranial to the inferiorcervical ganglion, or cranial to the middle cervical ganglion.

The signal application site may be at one or more interganglionicbranches selected from the group consisting of: between the middlecervical and T4 ganglia, between the middle cervical and T3 ganglia,between the middle cervical and T2 ganglia, and between the middlecervical and T1 ganglia, between the middle cervical and stellateganglia, between the middle cervical and inferior ganglia, between theinferior cervical and T4 ganglia, between the inferior cervical and T3ganglia, between the inferior cervical and T2 ganglia, between theinferior cervical and T1 ganglia, between the stellate and T4 ganglia,between the stellate and T3 ganglia, between the stellate and T2ganglia, between T1 and T4 ganglia, between T1 and T3 ganglia, betweenT1 and T2 ganglia, between T2 and T4 ganglia, between T2 and T3 ganglia,and between T3 and T4 ganglia. The signal application site may be at anyof these interganglionic branches in the left and/or right sympatheticchain. There may be one or more application sites on eachinterganglionic branch.

The application site may be at the ansae subclavia. The ansae subclaviain an interganglionic nerve branch that possesses nerve cords thatsurround the subclavian artery, and form the primary interconnectionbetween the stellate, middle cervical and the mediastinal ganglia (seeFIG. 1 ) [14,15]. The dorsal ansae subclavia arise as a craniomedialextension of the stellate ganglion and are usually shorter and thickerthan the ventral ansae, which loop anteriorly around the subclavianartery. There is anatomical heterogeneity in that each individual mayhave one or more ansae subclavia. For example, the ansae subclavia canexist as single or multiple nerve cords, and the right side tends tohave more nerve cords in total than the left. There are variationsaccording to the origin and termination of the loop, for example, insome individuals no distinct dorsal ansae can be seen because thestellate and the inferior-most middle cervical ganglia form a largeswelling. Thus, the signal application site may be at one or more of theansae subclavia.

In embodiments where the signal is applied below a predeterminedthreshold at the ansae subclavia, and the signal incites actionpotentials in the direction away from the heart, i.e. in the directionfrom the middle cervical ganglion to the stellate ganglion or the T1ganglion (depending on the individual, as mentioned above the inferiorcervical ganglion may have fused with the T1 ganglion in certainindividuals). This may result in refractoriness in the ganglia in thesympathetic chain, e.g. preferentially in the stellate/T1 ganglion, orin both the middle cervical ganglion and the stellate/T1 ganglion,leading to the reduction of sympathetic neural signals from the gangliato the heart.

The signal application site is preferably at or caudal to the ansaesubclavia along the sympathetic chain. This is because the ansaesubclavia represents the lowest nexus point in the cardiac nervoussystem hierarchy for sympathetic projection to the heart that isamenable to the neural interfacing element. From the ansae subclavia,the cardiac-related sympathetic nerves become more diffused so it ispractically more difficult to target them. The site of signalapplication may be at the junction between the dorsal and ventral ramiof the ansae subclavia adjacent to the stellate ganglion.

Preferably, the signal application site is cranial to the T3 ganglionalong the sympathetic chain, which includes the ansae subclavia. Minimalexogenous neural modulation disturbances to the T3 element and the morecaudal elements of the sympathetic chain is advantageous because theyare associated with sensory and sympathetic motor control of upper limb,neck and thoracic wall, so the risks for upper limb and thoracic wallpain syndromes and anhydrosis can be minimized. The invention thereforepreferably applies the signal to a cardiac-related sympathetic nerve atan interganglionic branch in the sympathetic chain that is cranial tothe T3 ganglion.

The signal application site is preferably between the T2 ganglion andthe ganglion cranial to T2, which may be the stellate ganglion or the T1ganglion. The specific anatomical structure that is modulated woulddepend on the anatomical arrangement of the individual. This region isamenable for neural interfacing element (e.g. electrode) attachment.Also, modulation of neural activity in this region minimizes adverse oroff-target effects, as explained above.

Thus, preferably, the signal application site is between the T1 and T2ganglia. According to the invention, when the invention involvesapplying a signal below a predetermined threshold at the sympatheticchain between the T1-T2 ganglia, and the signal incites actionpotentials which propagate preferentially in the direction away from theheart, i.e. from the T1 ganglion to the T2 ganglion, this may result inrefractoriness in the ganglia in the sympathetic chain, e.g.preferentially in the T2 ganglion, or in both the T1 and T2 ganglia,leading to the reduction of sympathetic neural signals from the gangliato the heart.

Preferably, the signal application site is between the inferior cervicaland T1 ganglia. According to the invention, when the signal is appliedbelow a predetermined threshold at the ansae subclavia, and the signalincites action potentials in the direction away from the heart, i.e. inthe direction from the inferior cervical ganglion to the T1 ganglion,this may result in refractoriness in the ganglia in the sympatheticchain, e.g. preferentially in the inferior cervical ganglion, or in boththe inferior cervical and T1 ganglia, leading to the reduction ofsympathetic neural signals from the ganglia to the heart.

The signal application site may be between the T2 and T3 ganglia.According to the invention, when the signal is applied below apredetermined threshold at the sympathetic chain between the T2-T3ganglia, and the signal incites action potentials which propagatepreferentially in the direction away from the heart, i.e. in thedirection from the T2 ganglion to the T3 ganglion, this may result inrefractoriness in the ganglia in the sympathetic chain, e.g.preferentially in the T3 ganglion, or in both the T2 and T3 ganglia,leading to the reduction of sympathetic neural signals from the gangliato the heart.

Ideally, the signal application site at the interganglionic branch isamenable to neural interfacing element. For example, the nerve isaccessible for the neural interfacing element, and is not obstructed byganglia, branching nerves, other nerves or blood vessels. For example,the interganglionic branch between the T1 and T2 is amenable to neuralinterfacing element (e.g. electrode) attachment. As well as beingaccessible, the T1-T4 region tends to be consistent from patient topatient, thus facilitating this site for general use. The T1-T4 andT1-T2 regions have been previously used as a point of intervention [16].

Plasticity exists for cardiac-related sympathetic nerves in theextracardiac intrathoracic neural circuits. For example, neuralremodeling including neuron cell body hypertrophy, increased fibrosis,and increased synaptic density have been shown to occur in the left andin both stellate ganglia in patients with cardiomyopathy and in ananimal model of myocardial infarction [17,18]. Thus, the exact site forsignal application may vary from human to human, but is nonetheless atan interganglionic branch between the intrathoracic ganglia in thesympathetic chain.

The sympathetic chain lies on either side of the vertebral column andessentially extends along its length. Thus, when the invention refers toa cardiac-related nerve in an interganglionic branch between theintrathoracic ganglia in the sympathetic chain, it may be referring tothe interganglionic branches in the right and/or left sympathetic chain.Hence, the electrical signal may be applied unilaterally or bilaterallyat cardiac-related nerves in interganglionic branches between theintrathoracic ganglia in the sympathetic chain. Modulation of neuralactivity of one instead of both sides may be sufficient for achievingbeneficial physiological effects. This is advantageous because itminimizes the interruption of neural activity, thereby minimizes anyadverse off-target effects. When applying the signal bilaterally atcardiac-related nerves in interganglionic branches between theintrathoracic ganglia in the sympathetic chain, the signal may beapplied sequentially or simultaneously.

For example, the signal application site may be at the right and/or theleft ansae subclavia.

The signal application site may be between the T1 and T2 ganglia in theright and/or the left sympathetic chain.

The signal application site may be between the T2 and T3 ganglia in theright and/or the left sympathetic chain.

The application sites of the cardiac-related nerve discussed above aresummarized in FIG. 3 .

Where the invention refers to a modified cardiac-related nerve, thisnerve is ideally present in situ in a subject.

Greater Splanchnic Nerve (GSN)

The invention aims to restore the foregut's homeostasis (e.g. glucosemetabolism) by modulating afferent-mediated decreases in centralsympathetic drive. To cause afferent-mediated decreases in centralsympathetic drive, the invention involves inciting action potentials ata certain site in a branch of the greater splanchnic nerve (GSN), andthis causes changes in the electrical properties of the ganglionic cellbodies adjacent to the signal application site (such as ganglionicrefractoriness), thereby resulting in reduced efferent sympatheticsignals to the foregut.

The splanchnic nerves carry fibers of the autonomic nervous system(visceral efferent fibers) and sensory fibers from various organs(visceral afferent fibers). All splanchnic nerves carry sympatheticfibers, except for the pelvic splanchnic nerves. The thoracic splanchnicnerves are recognized as medial branches from the lower seven thoracicsympathetic ganglia. They are pre-synaptic nerves of the sympatheticsystem, and include the GSN, the lesser splanchnic nerve, and the leastsplanchnic nerve. They pass through the diaphragm to send fibers to theceliac, aorticorenal, and superior mesenteric ganglia and plexuses (seeReference [19]). The GSN synapses at the suprarenal ganglion, and thentravels to the celiac ganglion where it synapses, and then travel to andinnervates the enteric nervous system of the foregut (see FIG. 2 ).

The GSN naturally projects sympathetic signals to the enteric nervoussystem of the foregut, stimulating glucose metabolism for example.Altering neural signaling in the GSN, e.g. the celiac plexus, has alsobeen shown to modulate sympatho-excitation, e.g. resulting in modulationof glucose control or mesenteric vascular resistance. For example, thereis evidence in the literature for hepatic sympathetic signaling to becontributory to type 2 diabetes, e.g. renal denervation technology byMetavention which focusses on hepatic sympathetic denervation forimproving glucose control. Reference [20] shows that signals from theduodenum via TRPV1 sensitive fibers are key to impaired glucose handlingand ablation of TRPV1 fibers using RTX improves OGTT profiles inSprague-dawley rats. The inventors have also observed that GSNdenervation is capable of improving glucose control [21]. There is alsoevidence in the literature to suggest that blocking sympathetic signalsin the celiac plexus leads to lowering of mesenteric vascular resistanceand as a result lowering of systemic blood pressure [22,23].

Examples of signal application sites at the GSN that are useful with theinvention are shown in FIG. 4 (e.g. (1) and (2)). These sites areamenable to surgical intervention and neural interfacing elementattachment.

In some embodiments of the invention, the signal application site may beat a branch of the GSN between the suprarenal and celiac ganglia (e.g.signal application site (2) in FIG. 4 ). When the electrical signalincites action potentials that propagate preferentially in the directionaway from the foregut, i.e. in the direction from the celiac ganglion tothe suprarenal ganglion, this may result in refractoriness in theganglia, e.g. preferentially in the suprarenal ganglion, or in both theceliac and the suprarenal ganglia, leading to the reduction ofsympathetic neural signals to the enteric nervous system of the foregut.This may lead to increasing glucose tolerance, thereby assisting intreating conditions associated with impaired glucose control. This mayalso lead to lowering of mesenteric vascular resistance that would bebeneficial for treating hypertension, heart failure with reducedejection fraction or heart failure with preserved ejection fraction.

In some embodiments of the invention, the signal application site may beat a branch of the GSN between the celiac ganglion and the foregut (e.g.signal application site (1) in FIG. 4 ). When the electrical signalincites action potentials that propagate preferentially in the directionaway from the foregut, i.e. in the direction from the foregut to theceliac ganglion, this may result in refractoriness in the celiacganglion, leading to the reduction of sympathetic neural signals fromthe celiac ganglion to the enteric nervous system of the foregut. Thismay lead to increasing glucose tolerance, thereby assisting in treatingconditions associated with impaired glucose control. This may also leadto lowering of mesenteric vascular resistance that would be beneficialfor treating hypertension, heart failure with reduced ejection fractionor heart failure with preserved ejection fraction.

There are two GSNs in the human body and, while signal application toeither (i.e. unilateral signal application) or both (i.e. bilateralsignal application) is possible according to the invention, the GSN ofparticular interest is the left GSN. The left GSN is more surgicallyaccessible.

Where the invention refers to a modified greater splanchnic nerve, thisnerve is ideally present in situ in a subject.

Modulation of Neural Activity

As explained above, the invention involves modulating afferent-mediateddecreases in central sympathetic drive, and this is achieved bymodulating the neural activity of a ganglion which leads to preferentialreduction of efferent sympathetic signals to its effector. Modulation ofneural activity, as used herein, is taken to mean that the signalingactivity of the nerve is altered from the baseline neural activity—thatis, the signaling activity of the nerve in the subject prior to anyintervention. As used herein, “neural activity” of a nerve means thesignaling activity of the nerve, for example the amplitude, frequencyand/or pattern of action potentials in the nerve. The term “pattern”, asused herein in the context of action potentials in the nerve, isintended to include one or more of: local field potential(s), compoundaction potential(s), aggregate action potential(s), and also magnitudes,frequencies, areas under the curve and other patterns of actionpotentials in the nerve or sub-groups (e.g. fascicules) of neuronstherein. The invention involves modulating the neural activity of atleast part of a nerve according to the invention. Modulation of neuralactivity may also be across the whole nerve.

The invention involves applying electrical signals to incite actionpotentials in the direction towards a particular ganglion that transmitssympathetic signals to an effector (i.e. to cause directionalstimulation of neural activity). Stimulation of neural activity, as usedherein, is taken to mean that the signaling activity of the nerve isincreased from the baseline neural activity. Directional stimulation, asused herein, is taken to mean an increase in signaling activity of thenerve from baseline neural activity preferentially in one directionalong the nerve axis.

As described herein, the invention involves modifying the neuralactivity of the sympathetic nerve and the ganglion. A way to create amodified sympathetic nerve and ganglion can involve three aspects. Thefirst aspect is to stimulate the neural activity of the nerve, resultingin the creation of action potentials which propagate in both directionsalong the nerve axis. The second aspect is to arrest or slow the actionpotentials in one direction. Then, the third aspect is when the actionpotentials propagating in the other direction are allowed to reach theadjacent ganglion. The action potentials modulate the neural activity ofthat ganglion such that it operates in a modified state, i.e. having areduced capacity to transmit sympathetic signals to the effector. Thus,the sympathetic nerve, to which the signal has been applied according tothe invention, is operating in a modified state.

These aspects are described in further detail below.

In the first aspect, a first electrical signal, in the form of atemporary external electrical field, when applied at a particular pointin the nerve (via a first electrode; anode), artificially modifies thedistribution of potassium and sodium ions within that point in thenerve, causing depolarization of the nerve membrane that would nototherwise occur. The depolarization of the nerve membrane caused by thetemporary external electrical field gives rise to de novo actionpotentials which propagate in opposite directions along the nerve axisaway from the point of the temporary external electrical field.

In the second aspect, a second electrical signal, also in the form of atemporary external electrical field, when applied at a second pointadjacent the first point in the nerve (via a second electrode; cathode),artificially modifies the distribution of potassium and sodium ionswithin that point in the nerve, causing hyperpolarization of the nervemembrane that would not otherwise occur. The hyperpolarization of thenerve membrane caused by the temporary external electrical field arrestsor slows the propagation of the de novo action potentials from passingalong the nerve axis beyond the point of the temporary externalelectrical field.

Then, in the third aspect, the de novo action potentials which propagatetowards the ganglion change the electrical properties of the ganglioniccell bodies. This may involve re-organization to silence the excitatorycell bodies and bring about homeostasis in the ganglionic cell bodies.One of the processes this might result in would be increasing therefractoriness of the ganglionic cell bodies that would make themresistant to incoming volleys from CNS. Hence, this is a ganglionoperating in a modified state. In this modified state, the ganglion hasa reduced capacity to transmit sympathetic signals to the effector.Hence, the sympathetic signals that would normally have been transmittedfrom the CNS to the effector via that ganglion would be reduced.

Where the invention refers to a modified sympathetic nerve and amodified ganglion, this nerve and ganglion are ideally present in situin a subject.

As it would be understood in the art, the creation generation of actionpotentials is based on the influence of electrical currents (e.g.charged particles, which may be one or more electrons in an electrodeattached to the nerve, or one or more ions outside the nerve or withinthe nerve, for instance) on the distribution of ions across the nervemembrane. According to the invention, the electrical currents areconfigured to apply a charge density per phase below a predeterminedthreshold.

One advantage of the invention is that modulation of the neural activityis reversible. For example, refractoriness in the ganglia of thesympathetic chain is reversible. Hence, the modulation of neuralactivity is not permanent. That is, upon cessation of the signal, neuralactivity in the nerve returns substantially towards baseline neuralactivity within 1-60 seconds, or within 1-60 minutes, or within 1-24hours (e.g. within 1-12 hours, 1-6 hours, 1-4 hours, 1-2 hours), orwithin 1-7 days (e.g. 1-4 days, 1-2 days). In some instances ofreversible modulation, the neural activity returns substantially fullyto baseline neural activity. That is, the neural activity followingcessation of the signal is substantially the same as the neural activityprior to the modulation (i.e. prior to the signal being applied). Hence,the nerve or the portion of the nerve has regained its capacity topropagate action potentials.

In other embodiments, modulation of the neural activity may besubstantially persistent. As used herein, “persistent” is taken to meanthat the modulated neural activity has a prolonged effect. That is, uponcessation of the signal, neural activity in the nerve remainssubstantially the same as when signal was being applied—i.e. the neuralactivity during and following a signal being applied is substantiallythe same. However, reversible modulation is preferred.

Charge Density Per Phase Below a Predetermined Threshold

The charge density per phase (C/cm²/phase) applied to nerve according tothe invention by the electrical signal is below a predeterminedthreshold. In particular, the charge density applied to the nerve by theelectrical signal is below the predetermined threshold for each andevery phase of the electrical signal.

The predetermined threshold is defined as the minimum charge density perphase required to produce sympatho-excitation responses that areassociated with sympatho-excitation in the effector. The predeterminedthreshold is denoted herein as ‘τ’.

In some embodiments, the predetermined threshold may be a predeterminedafferent threshold. The predetermined afferent threshold is determinedusing the electrode configuration in FIG. 5A, as is further discussedbelow. The predetermined afferent threshold is denoted herein as‘τ_(A)’.

In some embodiments, the predetermined threshold may be a predeterminedefferent threshold. The predetermined efferent threshold is determinedusing the electrode configuration in FIG. 5B, as is further discussedbelow. The predetermined efferent threshold is denoted herein as‘τ_(E)’.

It is known in the art that the predetermined efferent threshold τ_(E)is lower than the predetermined afferent threshold τ_(A). Thus, in someembodiments, the charge density per phase applied to nerve according tothe invention by the electrical signal may be above the predeterminedefferent threshold τ_(E) and below the predetermined afferent thresholdτ_(A).

In embodiments where the effector is the heart, the predeterminedthreshold may be defined as the minimum charge density per phaserequired to produce a cardiac response that is associated with cardiacsympatho-excitation, and the response comprises: a positive chronotropicresponse (e.g. increase in heart rate), a positive dromotropic response,a positive lusitropic response and/or a positive inotropic response.

In embodiments where the effector is the foregut, the predeterminedthreshold may be defined as the minimum charge density per phaserequired to produce responses that are associated withsympatho-excitation, e.g. increase in blood pressure, increase in heartrate, and/or increase in myocardial contractility.

Charge per phase applied to the nerve by the electrical signal isdefined as the integral of the current over one phase (e.g. over onephase of the biphasic pulse in the case of a charge-balanced biphasicpulse). Thus, charge density per phase applied to the nerve by theelectrical signal is the charge per phase per unit of contact areabetween at least one neural interfacing element (e.g. an electrode) andthe nerve, and also the integral of the current density over one phaseof the signal waveform. Put another way, the charge density per phaseapplied to the nerve by the electrical signal is the charge per phaseapplied to the nerve by the electrical signal divided by the contactarea between the at least one neural interfacing element and the nerve.

The electrical parameters for the signal of the predetermined thresholdare typically chosen such that for each individual, there was minimalchange in a physiological parameter.

For example, in embodiments where the effector is the heart, thephysiological parameter to be measured for determining the threshold maybe heart rate. In such embodiments, the predetermined threshold ischosen such that for each individual, there is minimal change in theheart rate during the on-phase of the signal application, but that withone additional step up in one electrical parameter (e.g. currentintensity), tachycardia would be reproducibly evoked.

For example, in embodiments where the target is the foregut, thephysiological parameter to be measured for determining the threshold maybe systemic blood pressure, heart rate and/or myocardial contractility.In such embodiments, the predetermined threshold is chosen such that foreach individual, there is minimal change in the systemic blood pressure,heart rate and/or myocardial contractility during the on-phase of thesignal application, but that with one additional step up in oneelectrical parameter (e.g. current intensity), increase in systemicblood pressure, increase in heart rate and/or increase in myocardialcontractility would be reproducibly evoked.

The predetermined threshold may vary according to the user of thedevice. The threshold may vary by one or more of: age, sex and generalhealth of the user. Thus, the predetermined threshold may be a valuethat is determined in the subject who will be receiving a signal tomodulate the neural activity of the as described herein, and so thepredetermined threshold would be specific to the subject.

Alternatively, the predetermined threshold may be a fixed value. Forexample, the predetermined threshold may be an average that has beendetermined across a group of subjects. The group of subjects may beage-specific, gender-specific, and/or disorder-specific. For example,subjects who suffer from or are at risk of a particular cardiacdisorder, as described herein.

The predetermined threshold may be ≤80 μC/cm²/phase. For example, thepredetermined threshold may be 5 μC/cm²/phase, 10 μC/cm²/phase, 15μC/cm²/phase, 20 μC/cm²/phase, 25 μC/cm²/phase, 30 μC/cm²/phase, 35μC/cm²/phase, 40 μC/cm²/phase, 45 μC/cm²/phase, 50 μC/cm²/phase, 55μC/cm²/phase, 60 μC/cm²/phase, 75 μC/cm²/phase, 80 μC/cm²/phase, or anyvalue between.

In some embodiments, the electrical signal used with the invention isconfigured to have a charge density per phase of between 0.1τ and 0.9τ.For example, the charge density per phase to be applied may be: between0.2τ and 0.8τ, between 0.3τ and 0.7τ, or between 0.4τ and 0.6τ. In otherembodiments, the charge density per phase to be applied may be: ≤0.1 τ,≤0.2τ, ≤0.3τ, ≤0.4τ, ≤0.5τ, ≤0.6τ, ≤0.7τ, ≤0.8τ, or ≤0.9τ. Alternativelyor additionally, the charge density per phase to be applied may be:≥0.1τ, ≥0.2τ, ≥0.3τ, ≥0.4τ, ≥0.5τ, ≥0.6τ, ≥0.7τ, ≥0.8τ, or ≥0.9τ.

Methods for Determining the Threshold As explained herein, thepredetermined threshold is determined by applying an electrical signalto the nerve with a particular electrode configuration.

Examples of electrode configurations for determining the predeterminedthreshold are shown in Reference [13] (i.e., the ‘cardiac’ and‘epilepsy’ electrode configurations). In particular, the ‘epilepsy’electrode configuration, which uses two electrodes with the cathodecephalad to the anode, determines the predetermined afferent thresholdTA. The ‘cardiac’ electrode configuration, which uses two electrodesarranged with the anode cephalad to the cathode, determines thepredetermined efferent threshold τ_(E).

The ‘epilepsy’ configuration, which is referred to herein as the ‘firstelectrode configuration’ is shown in FIG. 5A. The ‘cardiac’configuration, which is referred to herein as the ‘second electrodeconfiguration’ is shown in FIG. 5B.

Without wishing to be bound by theory, the predetermined afferentthreshold τ_(A) may be determined using at least two neural interfacingelements (e.g. electrodes) arranged in the configuration shown in FIG.5A by inciting action potentials that preferentially propagate away froman effector (i.e. in the afferent direction).

Referring to FIG. 5A, a first electrode 401 is positioned along thenerve axis adjacent to the second reference electrode 402, and arrangedsuch that the second reference electrode 402 is closer to the effector410 along the nerve axis than the first reference electrode 403.

When an electrical signal is applied to the first electrode 401 suchthat it becomes negatively charged (cathode) a depolarization of theaxon occurs generating an action potential, and when an electricalsignal is applied to the second electrode 402 such that it becomespositively charged (anode), a hyperpolarization of the axon can occurinhibiting the propagation of action potentials past the anode.

Under optimized conditions, the propagation of the action potentialsgenerated in the nerve is biased in the afferent direction.

Without wishing to be bound by theory, the predetermined efferentthreshold τ_(E) may be determined using at least two neural interfacingelements (e.g. electrodes) arranged in the configuration shown in FIG.5B by inciting action potentials that preferentially propagate towardsan effector (i.e. in the efferent direction).

Referring to FIG. 5B, a first electrode 403 is positioned along thenerve axis adjacent to the second electrode 404, and arranged such thatthe second electrode 404 is closer to the effector 410 along the nerveaxis than the first electrode 403. Put another way, the first electrodeis rostral along the axis of the nerve to the second electrode.

When an electrical signal is applied to the second electrode 404 suchthat it becomes negatively charged (cathode) a depolarization of theaxon occurs generating an action potential, and when an electricalsignal is applied to the first electrode 403 such that it becomespositively charged (anode), a hyperpolarization of the axon can occurinhibiting the propagation of action potentials past the anode. Underoptimized conditions, the propagation of the action potentials in thenerve is biased in the efferent direction.

In an example, the predetermined threshold may be determined in asubject by applying to the nerve electrical signals with increasingaverage current intensity (mA) at small intervals (e.g. increments of0.1 mA), each for a constant duration (e.g. 2 min), at a constantfrequency (e.g. 1 Hz), and with a constant area of contact between theat least two neural interfacing elements and the nerve (e.g. 1 mm²).Then, identifying the minimum average current intensity (e.g. 1 mA) atwhich a response in the heart is produced. The response may be indicatedby statistically significant changes in one or more responses of theheart, as described above. Examples of the small intervals of theaverage current intensity that may be tested are 0.05 mA, 0.1 mA, 0.2mA, or 0.5 mA.

By way of a further example, the predetermined threshold may bedetermined in a subject by applying to the nerve electrical signals withincreasing frequency (Hz) at small intervals (e.g. increments of 0.1Hz), each for a constant duration (e.g. 2 min), at a constant averagecurrent intensity (e.g. 1 mA), and with a constant area of contactbetween the at least two neural interfacing elements and the nerve (e.g.1 mm²). Then, identifying the maximum frequency (e.g. 1 Hz) at which aresponse in the heart is produced. The response may be indicated bystatistically significant changes in one or more responses of the heart,as described above. Examples of the small intervals of the frequencythat may be tested are 0.05 Hz, 0.1 Hz, 0.2 Hz, 0.5 Hz, or 1 Hz.

By way of a further example, the predetermined threshold may bedetermined in a subject by applying to the nerve electrical signals withincreasing the duration (e.g. increments of 10 sec), at a constantaverage current intensity (e.g. 1 mA), at a constant frequency (e.g. 1Hz) and with a constant area of contact between the at least two neuralinterfacing elements and the nerve (e.g. 1 mm²). Then, identifying theminimum duration (e.g. 2 min) at which a response in the heart isproduced. The response may be indicated by statistically significantchanges in one or more responses of the heart, as described above.Examples of the duration that may be tested are <10 sec, <30 sec, <1min, <2 min, or <5 min. The duration tested may be, for example, 1 sec,2 sec, 5 sec, 10 sec, or 15 sec.

It would be of course understood in the art that the electrical signalapplied to the nerve for determining the predetermined threshold wouldbe within clinical safety margins (e.g. suitable for maintaining nervesignaling function, suitable for maintaining nerve integrity, andsuitable for maintaining the safety of the subject). The electricalparameters within the clinical safety margin would typically bedetermined by pre-clinical studies. For example, the frequency of thesignal is not higher than 200 Hz, 150 Hz, 100 Hz, or 50 Hz. For example,the average current intensity of the signal is not larger than 50 mA, 25mA, or 10 mA. For example, the duration is not more than 24 h, 10 h, 5h, or 1 h.

Neural Interfacing Elements

As mentioned above, the invention involves modulating a nerve byinciting action potentials that propagate preferentially away from aneffector, towards a ganglion (i.e. in the afferent direction). This maybe achieved using at least two neural interfacing elements, as discussedabove and in reference [20]. Thus, a system of the invention preferablycomprises at least two neural interfacing elements for modulation of theneural activity in a nerve according of the invention.

The at least two neural interfacing elements of the system areconfigured to apply the electrical signals to a nerve, or a partthereof. However, the skilled person will appreciate that electricalsignals are just one way of implementing the invention.

The neural interfacing elements are preferably electrodes (e.g.electrode 109, 401, 402). Each neural interfacing element may compriseone or more conducting materials (not limited to non-reactive metals,graphene and/or conductive polymers). Each neural interfacing elementdefines one contact pad (e.g. an electrical contact pad) between thesystem of the invention and the nerve. Thus, one neural interfacingelement may be a single unipolar electrode. Two neural interfacingelements may be two unipolar electrodes, also referred to in the art asa bipolar electrode. Three neural interfacing elements may be threeunipolar electrodes, also referred to in the art as a tripolarelectrode, etc.

To incite action potentials that propagate preferentially away from aneffector, towards a ganglion (i.e. in the afferent direction), the atleast two neural interfacing elements are arranged in the configurationshown in FIG. 5A.

Referring to FIG. 5A, a first electrode 401 is positioned along thenerve axis adjacent to the second reference electrode 402, and arrangedsuch that the second reference electrode 402 is closer to the effector410 along the nerve axis than the first reference electrode 403.

When an electrical signal is applied to the first electrode 401 suchthat it becomes negatively charged (cathode) a depolarization of theaxon occurs generating an action potential, and when an electricalsignal is applied to the second electrode 402 such that it becomespositively charged (anode), a hyperpolarization of the axon can occurinhibiting the propagation of action potentials past the anode. Underoptimized conditions, the propagation of the action potentials generatedin the nerve is biased in the afferent direction.

Effectors suitable for use with the first electrode configuration ofFIG. 5A include the heart, and the foregut. Any of the signalapplication sites discussed above are suitable for targeting one ofthese effectors using the first electrode configuration.

In some embodiments, the first electrode configuration of FIG. 5A may beadapted to improve the biasing of action potentials such that the actionpotentials travel preferentially in the afferent direction. Theseembodiments are shown in FIGS. 6A-6C.

In some embodiments, as shown in FIG. 6A, the surface area of the firstelectrode 401 is different to the surface area of the second electrode402. In particular, the surface area of the first electrode 401 isadapted to be larger than the surface area of the second electrode 402to concentrate charge density under the second electrode 402, thusstrengthening the hyperpolarization of the nerve without increasedenergy requirements.

For cuff type electrodes that fully circumvent the nerve, the size ofthis surface area can be calculated by multiplying π (i.e. 3.14159) bythe internal diameter and width the electrode (i.e. the first electrode401 or the second electrode 402). Since the internal diameter of thefirst electrode 401 and the second electrode 402 is fixed by thediameter of the nerve, the surface area of each of the first electrode401 and the second electrode 402 which is contactable with the nerve isadjusted by changing the width of the electrode. The width of each ofthe first electrode 401 and the second electrode 402 being defined asthe distance the electrode spans along the longitudinal axis of thenerve. Thus, in such embodiments, the width of the first electrode 401is greater than the width of the second electrode 402. For example, thewidth of the first electrode 401 may be at least twice the width of thesecond electrode 402.

In such embodiments, the width of the first electrode 401 may also beless than or equal to five times the width of the second electrode 402.This is to avoid stimulating additional action potentials under thesecond electrode 402.

Thus, in such embodiments, the width of the second electrode 402 may beset at any value between the upper and lower limits described above. Forexample, the width of the first electrode 401 may be 2, 2.5, 3.0, 3.5,4.0, 4.5 or 5.0 times the width of the second electrode 402.

In other embodiments, as shown in FIG. 6B, one of the first electrode401 and second electrode 402 may be recessed away from the nerve, asdiscussed in [24]. In particular, the first electrode 401 is radiallyrecessed away from the nerve to reduce extracellular potential at thenerve interfacing the second electrode 401 compared to the extracellularpotential at the nerve interfacing the second electrode 402 which is notrecessed away.

In such embodiments, the first electrode configuration may includeinsulation circumventing the first electrode 401 and second electrode402. The insulation circumventing the second electrode 402 may bethinner than the insulation circumventing the first electrode 401. Thismay decrease the impedance of an electrical return path outside of theinsulation compared to at the neural interface, increasing thepossibility of forming virtual anodes and cathodes. The radiallyrecessed second electrode 402 has a reduced extracellular potentialcompared to that of first electrode 401 which reduces the formation of avirtual cathode between the first electrode configuration and the brain,allowing directionality to be conveyed via a virtual anode proximalbetween the first electrode configuration and the effector.

In further embodiments, as shown in FIG. 6C, the insulationcircumventing the first electrode 401 and second electrode 402 may beasymmetric, see, for example [24,25]. In particular, the surface area ofthe insulation contactable with the nerve either side of the firstelectrode arrangement is unequal such that the surface area adjacent thefirst electrode 401 is greater than the surface area adjacent the secondelectrode 402. In other words, the neural interface comprises first andsecond insulation regions on either side of the electrodes which issituated off-center to the interface such that the insulation regionshave different lengths.

In such embodiment, the asymmetry of the insulation has the effect ofreducing the generation of virtual anodes and virtual cathodes whichnegate directionality.

It will be appreciated by a person skilled in the art that theembodiments of FIGS. 6A, 6B and 6C may be combined in any way to improvethe biasing of action potentials such that the action potentials travelpreferentially in the afferent direction. For example, the imbalancedsurface area electrodes of FIG. 6A is preferably circumvented by theasymmetric insulation of FIG. 6C.

Other suitable electrode configurations for inciting action potentialsthat propagate preferentially away from the effector, towards a ganglion(i.e. in the afferent direction) are discussed in Reference [11]. Thus,in some embodiments, only one neural interfacing element (e.g. oneelectrode) may be required. In other embodiments, at least three neuralinterfacing elements (e.g. three electrodes) may be used.

In some embodiments, one of the electrode configurations described aboveis positioned on a neural interface (e.g. neural interface 108). In suchembodiments, the neural interface is positioned on the nerve on oraround the nerve at one of the sites previously discussed (i.e. thoseshown in FIG. 3 and FIG. 4 ) suitable for the effector. Thus, forexample, there may be two, three, four, or more neural interfacingelements for applying a signal at a site. In such embodiments, theneural interfacing elements may be positioned on the neural interfacesuch that, in use, the neural interfacing elements are locatedtransversely along the axis of the nerve.

The plurality of electrodes at a single site may be insulated from oneanother by a non-conductive biocompatible material. To this end, theneural interface may comprise a non-conductive biocompatible materialwhich is spaced transversely along the nerve when the device is in use.

In some embodiments, the at least two neural interfacing elements usedto apply a signal to the nerve to incite action potentials thatpropagate preferentially away from the effector, towards a ganglion(i.e. in the afferent direction) for modulating neural activity in thenerve, may also be used for determining the predetermined threshold.

In some embodiments, the at least two neural interfacing elements mayalso be used for determining the predetermined afferent threshold τ_(A).In such embodiments, the at least two neural interfacing elements may bearranged according to the ‘first electrode configuration’ shown in FIG.5A. Using this configuration, the predetermined afferent threshold τ_(A)is determined according to one of the methods discussed above. Then, asignal is applied to the nerve below the predetermined threshold formodulating neural activity in the nerve. Suitable electrical parametersfor this signal are discussed in detail below.

In some embodiments, the at least two neural interfacing elements mayalso be used for determining the predetermined efferent threshold τ_(E).In such embodiments, the at least two neural interfacing elements may bearranged according to the ‘second electrode configuration’ shown in FIG.5B. Using this configuration, the predetermined efferent threshold τ_(E)is determined according to one of the methods discussed above. Then, toapply a signal to the nerve which generates action potentials thatpropagate preferentially away from the effector, towards a ganglion, thepolarity of each of the electrodes is switched such that the cathodebecomes an anode, and the anode becomes a cathode, where switching mayinvolve applying a different signal to the electrodes via a signalgenerator. The electrodes are consequently in the first electrodeconfiguration shown in FIG. 5A. Using this configuration, the electrodescan apply a signal to the nerve to incite action potentials thatpropagate preferentially away from the effector, towards a ganglion(i.e. in the afferent direction) for modulating neural activity in thenerve. Suitable electrical parameters for this signal are discussed indetail below.

In some embodiments, the system may comprise a plurality of neuralinterfaces. For example, there may be two, three or more neuralinterfaces.

The plurality of neural interfaces may be used for applying a signal tomultiple sites on the nerve, each neural interface corresponding to asite on the nerve and comprising one of the electrode configurationsdescribed above. In some embodiments, the sites may be each be locatedat a different interganglionic branches of the nerve, or at aninterganglionic branch and between a ganglion and an effector. In otherwords, there may be a plurality of neural interfaces, each located atdifferent interganglionic branches of the nerve, or at aninterganglionic branch and between a ganglion and an effector. In otherembodiments, there may be one or more sites for applying a signal ateach interganglionic branch of the nerve and/or between a ganglion andthe effector. In other words, there may be a plurality of neuralinterfaces located a single interganglionic branch of the nerve, orbetween a ganglion and an effector. A combination of the embodimentsabove is also possible. The site for applying a signal can be at any ofthe interganglionic branches at the left and/or right sympatheticchains.

Alternatively or additionally, one of the plurality of neural interfacesmay be used for determining the predetermined threshold. In suchembodiments, the neural interface may comprise the first electrodeconfiguration shown in FIG. 5A or the second electrode configuration asshown in FIG. 5B. In some embodiments, the neural interface fordetermining the predetermined threshold may be located at a differentinterganglionic branch of the nerve than the neural interface formodulation of neural activity. In other embodiments, neural interfacefor determining the predetermined threshold may be located at aninterganglionic branch whilst the neural interface for modulation islocated between a ganglion and an effector, or vice versa. In otherembodiments, neural interface for determining the predeterminedthreshold may be located at the same interganglionic branch of thenerve, or at the same location between a ganglion and an effector, asthe neural interface for modulation of neural activity.

In a first exemplary embodiment, as shown in FIG. 7A, a neural interface108 at a site on the branch between T1-T2 ganglia. In this embodiment,the neural interface 108 may be suitable for modulating neural activityof the nerve only, or may be suitable for modulating neural activity ofthe nerve and for determining the predetermined threshold, as discussedabove. In this first exemplary embodiment, the effector is the heart,and the action potentials propagate preferentially towards the T2ganglion (i.e. in the afferent direction).

In a second exemplary embodiment, shown in FIG. 7B, a first neuralinterface 108 is at a first site between T1-T2 ganglia, the first neuralinterface suitable for modulating neural activity of the nerve. There isalso a second neural interface 208 at a second site between T2-T3ganglia for determining the predetermined threshold. In this secondexemplary embodiment, the effector is the heart, and the actionpotentials for modulation of neural activity propagate preferentiallytowards the T2 ganglion (i.e. in the afferent direction).

In a third exemplary embodiment, as shown in FIG. 8A, a neural interface108 is at a site on the branch between the suprarenal ganglion and theceliac ganglion. In this embodiment, the neural interface 108 may besuitable for modulating neural activity of the nerve only. In this thirdexemplary embodiment, the effector is the foregut, and the actionpotentials for modulation of neural activity propagate preferentiallytowards the suprarenal ganglion (i.e. in the afferent direction).

In a fourth exemplary embodiment, shown in FIG. 8B, a first neuralinterface 108 is at a first site between the suprarenal ganglion and theceliac ganglion, the first neural interface suitable for modulatingneural activity of the nerve. There is also a second neural interface208 at a second site between the celiac ganglion and the foregut fordetermining the predetermined threshold. In this fourth exemplaryembodiment, the effector is the foregut, and the action potentials formodulation of neural activity propagate preferentially towards thesuprarenal ganglion (i.e. in the afferent direction).

Typically, the electrode applies the electrical signal by exerting anelectrical field across the nerve bundle, and hence applying theelectrical signal to many nerve fibers within the bundle. This generatesmultiple action potentials in each nerve fiber, and the combination ofthese action potentials may be called a compound action potential.

In some embodiments, the at least one neural interface and/or at leastone electrode is configured to at least partially circumvent the nerve.In some embodiments, the at least one neural interface and/or at leastone electrode is configured to fully circumvent the nerve, which mayform a cuff.

Electrodes may be shaped as one of: a rectangle, an oval, an ellipsoid,a rod, a straight wire, a curved wire, a helically wound wire, a barb, ahook, or a cuff. In addition to the one or more electrodes which, inuse, is located on, or around a nerve according to the invention, theremay also be a larger indifferent electrode placed in the adjacenttissue.

Electrodes may have a surface area in contact with the nerve between 0.5mm² and 5 mm², preferably between 0.75 mm² and 1 mm².

The electrodes may be coupled to an implantable device 106 of system 116via electrical leads 107 (see FIG. 9 ). Alternatively, implantabledevice 106 may be directly integrated with the electrodes 109 withoutleads. In any case, implantable device 106 may comprise DC currentblocking output circuits, optionally based on capacitors and/orinductors, on all output channels (e.g. outputs to the electrodes 109,or physiological sensor 111).

In some embodiments, electrodes may be used for recording neuralactivity of the sympathetic chain. These recording electrodes may bepositioned on a neural interface with the at least two neuralinterfacing elements. Alternatively, recording electrodes may bepositioned on a separate neural interface from the at least two neural.For example, in the embodiment as described in FIG. 6B, the neuralinterface between T2-T3 may have at least one recording electrode forrecording neural activity of the sympathetic chain. Recording electrodesare discussed further below.

A System According to the Invention

The invention involves applying at least one electrical signal via theat least two neural interfacing elements discussed above placed insignaling contact with a nerve according to the invention. The signal isan electrical signal, which may be, for example, a voltage or currentsignal.

A system 116 according to the invention comprises a device which may beimplantable (e.g. implantable device 106 of FIG. 9 ). The implantabledevice comprises at least two neural interfacing elements (e.g.electrode 109), suitable for placement on, or around a nerve accordingto the invention. The system may also comprises a processor (e.g.microprocessor 113) coupled to the at least two neural interfacingelements.

The system 116 may comprise an implantable device 106 which may compriseat least one signal generator 117. The signal generator 117 may comprisea voltage source or a current source, configured to apply a voltagesignal or a current signal respectively. The various components of thesystem are preferably part of a single physical device, either sharing acommon housing or being a physically separated collection ofinterconnected components connected by electrical leads (e.g. leads107). As an alternative, however, the invention may use a system inwhich the components are physically separate, and communicatewirelessly. Thus, for instance, the at least two neural interfacingelements (e.g. electrode 109) and the implantable device (e.g.implantable device 106) can be part of a unitary device, or together mayform a system (e.g. system 116). In both cases, further components mayalso be present to form a larger system (e.g. system 100).

Signal Parameters

In the present invention, a signal generator 117, such as a voltage orcurrent source, is configured to apply at least one electrical signal toa nerve according to the invention which has a charge density per phasebelow the predetermined threshold to modulate neural activity in thenerve.

In some embodiments, the electrical signal used with the invention maybe defined by the combination of the predetermined threshold and one ormore signal parameters. The predetermined threshold, in turn, may bedefined by the combination of the charge density per phase and the oneor more signal parameters (e.g. waveform, frequency, and amplitude).

The relationship between the charge density per phase applied to thenerve by the electrical signal and the signal parameters is discussedabove. The skilled person is therefore able to calculate the chargedensity per phase supplied by a particular set of signal parameters.Accordingly, the charge density per phase applied to the nerve by theelectrical signal may be varied by altering one or more signalparameters, e.g. waveform, frequency, and amplitude.

Waveform

The electrical signal comprises a direct current (DC) waveform, or analternating current (AC) waveform, or both a DC and an AC waveform.

In some embodiments, the waveform is a charge-balanced DC waveform witha constant average current intensity. As used herein, “charge-balanced”in relation to a DC current is taken to mean that the positive ornegative charge applied to the nerve as a result of a DC current beingapplied is balanced by the introduction of the opposite charge in orderto achieve overall (net) neutrality. The initial charge applied isreferred to herein as the “charge phase” and the opposite charge isreferred to herein as a “recharge phase”. The charge phase plus therecharge phase represent one phase of the signal, which may be repeatedto form the charge-balanced DC waveform. The charge phase may have aduration between 2 and 5 times that of the recharge phase.

In other embodiments, the AC waveform comprises one or more pulsetrains, each with a defined pulse width. The pulses are preferablysquare pulses. Other pulse waveforms such as sawtooth, sinusoidal,triangular, trapezoidal, quasitrapezodial or complex waveforms may alsobe used with the invention. In certain embodiments, quasitrapezodialwaveforms are particularly useful, e.g. when applying the electricalsignal for long durations (e.g. >0.5 ms).

The pulse width may be ≤2 ms, preferably between 0.01 and 2 ms(including, if applicable, both positive and negative phases of thepulse, in the case of a charge-balanced biphasic pulse). For example,the pulse width may be: ≤0.05 ms, ≤0.1 ms, ≤0.2 ms, ≤0.5 ms, ≤1 ms, ≤1.5ms, or ≤2 ms. Alternatively or additionally, the pulse width may be:≥0.05 ms, ≥0.1 ms, ≥0.2 ms, ≥0.5 ms, ≥1 ms, or ≥1.5 ms. The pulse widthmay additionally be limited by the frequency.

The pulses may be biphasic pulses. The term “biphasic” refers to asignal which applies to the nerve over time both a positive and negativecharge. The biphasic pulses are preferably charge-balanced. The term“charge-balanced” in relation to a pulse train is taken to mean that thepositive charge and negative charge applied by the signal over the pulseduration is equal. Alternatively, the pulses may be monophasic pulses.

The electrical signal may be a charge-balanced signal. A charge-balancedsignal refers to a signal which, over a period of time, applies equalamounts (or thereabouts) of positive and negative charge to the nerve.

In some embodiments, the pulses may be charge-balanced. Thecharge-balanced pulses may be symmetric or asymmetric. A symmetric pulseis a pulse where the waveform when applying a positive charge to thenerve is symmetrical to the waveform when applying a negative charge tothe nerve. An asymmetric pulse is a pulse where the waveform whenapplying a positive charge to the nerve is not symmetrical with thewaveform when applying a negative charge to the nerve.

In some embodiments, the waveform is a pulse train with charge-balancedbiphasic pulses, e.g. square pulses.

Frequency

Frequency is defined as the reciprocal of the phase duration (i.e.1/phase). The frequency for use with the invention is less than 30 Hz,and preferably less than 10 Hz such that action potentials in the nerveare stimulated (rather than inhibited). For example, the frequency maybe between 0.01 and 10 Hz, or between 0.01 and 5 Hz, or between 0.01 and2 Hz. In other examples, the frequency may be: ≤1 Hz, ≤2 Hz, ≤3 Hz, ≤4Hz, ≤5 Hz, ≤6 Hz, ≤7 Hz, ≤8 Hz, or ≤9 Hz. Additionally or alternatively,the frequency may be: ≥1 Hz, ≥2 Hz, ≥3 Hz, ≥4 Hz, ≥5 Hz, ≥6 Hz, ≥7 Hz,≥8 Hz, or ≥9 Hz.

In some embodiments where the waveform is a charge-balanced DC waveform,the frequency represents the number of charge and recharge phases persecond. For example, a frequency of 1 to 10 Hz results in a number ofcharge and recharge phases between 1 and 10.

In some embodiments where the waveform is a pulse train, the pulses areapplied at intervals according to the above-mentioned frequencies. Forexample, a frequency of 1 to 10 Hz results in a pulse interval between 1pulse per second and 10 pulses per second, within a given pulse train.

Amplitude

For the purpose of the invention, and in keeping with the art, theamplitude is referred to herein in terms of average current intensity.An electrical signal suitable for the invention has an average currentintensity of less than 10 mA, preferably between 10 μA and 10 mA.

In embodiments where the waveform is a pulse train with charge-balancedbiphasic square pulses, the average current intensity may be between 500μA to 10 mA. For example, the average current intensity may be: ≤1 mA,≤2 mA, ≤3 mA, ≤4 mA, ≤5 mA, ≤6 mA, ≤7 mA, ≤8 mA, ≤9 mA, or ≤10 mA.Additionally or alternatively, the average current intensity may be: ≥1mA, ≥2 mA, ≥3 mA, ≥4 mA, ≥5 mA, ≥6 mA, ≥7 mA, ≥8 mA, or ≥9 mA.

In embodiments where the waveform is a DC waveform with a constantaverage current intensity, the average current intensity may be between10 μA to 500 μA. For example, the average current intensity may be: ≤50mA, ≤100 mA, ≤150 mA, ≤200 mA, ≤250 mA, ≤300 mA, ≤350 mA, ≤400 mA, 450mA or ≤500 mA. Alternatively or additionally, the amplitude may be: ≥10mA, ≥50 mA, ≥100 mA, ≥150 mA, ≥200 mA, ≥250 mA, ≥300 mA, ≥350 mA, ≥400mA or ≥450 mA.

The signal generator 117 may be pre-programmed to apply one or moresignals with signal parameters falling within the ranges discussedabove. Alternatively, the signal generator 117 may be controllable toadjust one or more of the signal parameters discussed above whileensuring that the charge density per phase applied is below thepredetermined threshold. Control may be open loop, wherein the operatorof the implantable device 106 may configure the signal generator usingan external controller (e.g. controller 101), and warnings may be issuedto the operator if the charge density per phase applied is not below thepredetermined threshold. Control may alternatively or additionally beclosed loop, wherein signal generator modifies the signal parameters inresponse to one or more responses in the effector. Open loop and closedloop control of signal parameters is further described below.

The signal may be applied continuously, or periodically (i.e. for aspecific duration), as is further discussed below.

It will be appreciated by the skilled person that the signal parametersof an applied electrical signal necessary to achieve the intendedmodulation of the neural activity will depend upon the positioning ofthe electrode and the associated electrophysiological characteristics(e.g. impedance). It is within the ability of the skilled person todetermine the appropriate variations in signal parameters for achievingthe intended modulation of the neural activity in a given subject.

Electrical signals applied according to the invention are ideallynon-destructive. As used herein, a “non-destructive signal” is a signalthat, when applied, does not irreversibly damage the underlying neuralsignal conduction ability of the nerve. That is, application of anon-destructive signal maintains the ability of the nerve or fibersthereof, or other nerve tissue to which the signal is applied, toconduct action potentials when application of the signal ceases, even ifthat conduction is in practice artificially increased as a result ofapplication of the non-destructive signal.

It would be of course understood in the art that the electrical signalsapplied to the nerve would be within clinical safety margins (e.g.suitable for maintaining nerve signaling function, suitable formaintaining nerve integrity, and suitable for maintaining the safety ofthe subject). The electrical parameters within the clinical safetymargin would typically be determined by pre-clinical studies. Forexample, the frequency of the signal is not higher than 200 Hz, 150 Hz,100 Hz, or 50 Hz. For example, the average current intensity of thesignal is not larger than 50 mA, 25 mA, or 10 mA. For example, theduration is not more than 24 h, 10 h, 5 h, or 1 h.

Microprocessor

The implantable device 106, may comprise a processor, for examplemicroprocessor 113. Microprocessor 113 may be responsible for triggeringthe beginning and/or end of the signals applied to a nerve according tothe invention by the at least two neural interfacing elements.Optionally, microprocessor 113 may also be responsible for generatingand/or controlling the signal parameters of the signal such that thecharge density per phase applied to the nerve is below the predeterminedthreshold.

Microprocessor 113 may be configured to operate in an open-loop fashion,wherein a pre-defined signal (e.g. as described above) is applied to thenerve at a given periodicity (or continuously) and for a given duration(or indefinitely) with or without an external trigger, and without anycontrol or feedback mechanism. Alternatively, microprocessor 113 may beconfigured to operate in a closed-loop fashion, wherein a signal isapplied based on a control or feedback mechanism, and such that thecharge density per phase applied to the nerve is below the predeterminedthreshold. As described elsewhere herein, the external trigger may be anexternal controller 101 operable by the operator to initiate applicationof a signal.

Microprocessor 113 of the implantable device 106, may be constructed soas to generate, in use, a preconfigured and/or operator-selectablesignal that is independent of any input. In other embodiments, however,microprocessor 113 is responsive to an external signal, for exampleinformation (e.g. data) pertaining to one or more responses associatedwith sympatho-excitation of an effector.

Microprocessor 113 may be triggered upon receipt of a signal generatedby an operator, such as a physician or the subject in which theimplantable device 106 is implanted. To that end, the implantable device106 may be part of a system which additionally comprises an externalsystem 118 comprising a controller 101. An example of such a system isdescribed below with reference to FIG.

9.

External system 118 of system 100 is external to system 116 and externalto the subject, and comprises controller 101. Controller 101 may be usedfor controlling and/or externally powering system 116. To this end,controller 101 may comprise a powering unit 102 and/or a programmingunit 103. The external system 118 may further comprise a powertransmission antenna 104 and a data transmission antenna 105, as furtherdescribed below.

The controller 101 and/or microprocessor 113 may be configured to applyany one or more of the above signals to the nerve periodically orcontinuously. Periodic application of a signal involves applying thesignal in an (on-off)_(n) pattern, where n≥1. For instance, the signalcan be applied continuously for a duration of at least 5 days,optionally at least 7 days, before ceasing for a period (e.g. 1 day, 2days, 3 days, 1 week, 2 weeks, 1 month), before being again appliedcontinuously for another duration of at least 5 days, etc. Thus thesignal is applied for a first time period, then stopped for a secondtime period, then reapplied for a third time period, then stopped for afourth time period, etc. In such an embodiment, the first, second, thirdand fourth periods run sequentially and consecutively. The duration ofthe first, second, third and fourth time periods is independentlyselected. That is, the duration of each time period may be the same ordifferent to any of the other time periods. In certain such embodiments,the duration of each of the first, second, third and fourth time periodsmay be any time from 1 second (s) to 10 days (d), 2s to 7d, 3s to 4d, 5sto 24 hours (24 h), 30 s to 12 h, 1 min to 12 h, 5 min to 8 h, 5 min to6 h, 10 min to 6 h, 10 min to 4 h, 30 min to 4 h, or 1 h to 4 h. Incertain embodiments, the duration of each of the first, second, thirdand fourth time periods is 5 s, 10 s, 30 s, 60 s, 2 min, 5 min, 10 min,20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h,7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19h, 20 h, 21 h, 22 h, 23 h, 24 h, 2 d, 3 d, 4 d, 5 d, 6 d, or 7 d.

In certain embodiments, the signal is applied by controller 101 and/ormicroprocessor for a specific amount of time per day. In certain suchembodiments, the signal is applied for a duration of 10 min, 20 min, 30min, 40 min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h,9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h,21 h, 22 h, or 23 h per day. In certain such embodiments, the signal isapplied continuously for the specified amount of time. In certainalternative such embodiments, the signal may be applied discontinuouslyacross the day, provided the total time of application amounts to thespecified time.

Continuous application may continue indefinitely, e.g. permanently.Alternatively, the continuous application may be for a minimum period,for example the signal may be continuously applied for at least 5 days,or at least 7 days.

Whether the signal applied to the nerve is controlled by controller 101,or whether the signal is continuously applied directly by microprocessor113, although the signal might be a series of pulses, the gaps betweenthose pulses do not mean the signal is not continuously applied.

For preventive use, a subject at risk of developing cardiac dysfunctionmay be subjected to signal application for x min at regular intervals,wherein x =≤3 min, ≤5 min, ≤10 min, ≤20 min, ≤30 min, ≤40 min, ≤50 min,≤60 min, ≤70 min, ≤80 min , ≤90 min, ≤120 min, or ≤240 min. The intervalmay be once every day, once every 2 days, once every 3 days etc. Theinterval may be more than once a day, e.g. twice a day, three times aday etc.

In certain embodiments, the signal is applied only when the subject isin a specific state e.g. only when the subject is awake, only when thesubject is asleep, prior to and/or after the ingestion of food, prior toand/or after the subject undertakes exercise, etc.

The various embodiments for timing for modulation of neural activity inthe nerve can all be achieved using controller 101 in a system of theinvention.

The controller 101 and/or microprocessor 113 may include means fordetermining the charge density per phase supplied to the nerve in thetime period before the neural activity of the nerve returns to baselineactivity. The controller 101 and/or microprocessor 113 may additionallyinclude means for estimating the charge density per phase supplied tothe nerve by a set of signal parameters.

Other Components of the System Including the Implantable Device

In addition to the aforementioned neural interfacing element (e.g.electrode 109), neural interface 108, and microprocessor 113, the system116 may comprise one or more of the following components: implantabletransceiver 110; physiological sensor 111; power source 112; memory 114(otherwise referred to as a non-transitory computer-readable storagedevice); and physiological data processing module 115. Additionally oralternatively, the physiological sensor 111; memory 114; andphysiological data processing module 115 may be part of a sub-systemexternal to the system 116. Optionally, the external sub-system may becapable of communicating with the system, for example wirelessly via theimplantable transceiver 110.

In some embodiments, one or more of the following components may becontained in the implantable device 106: power source 112; memory 114;and a physiological data processing module 115.

The power source 112 may comprise a current source and/or a voltagesource for providing the power for the signal generator 117. The powersource 112 may also provide power for the other components of theimplantable device 106 and/or system 116, such as the microprocessor113, memory 114, and implantable transceiver 110. The power source 112may comprise a battery, the battery may be rechargeable. The implantabledevice 106 and/or system 116 may be powered by inductive powering or arechargeable power source.

It will be appreciated that the availability of power is limited inimplantable devices, and the invention has been devised with thisconstraint in mind. The invention in particular modulates a nerveaccording to the invention with an electrical signal with a chargedensity per phase below a predetermined threshold, where the thresholdis defined as the minimum charge density per phase reducesympatho-excitation in the effector in the subject. This is differentfrom conventional devices, such as that in reference [9] which aim toevoke a response associated with sympatho-excitation of an effector bymodulating the nerve above the predetermined threshold, and hencerequire greater amounts of electrical charge than the invention for thetreatment of one of the diseases discussed below (e.g. cardiacdysfunction). The low electrical charge required for treatment by theinvention results in a lower amount of electrical energy being requiredfor the treatment. This is advantageous as it reduces the burden on theimplantable device and/or system for generating power, allowing thedevice and/or system to be smaller and lighter. Furthermore, in the casethat the power source is not powered by inductive powering, the powersource does not need to be changed as often. Changing a power sourcesuch as a battery in implanted devices such as the invention can berisky as it generally involves surgery. Methods for converting a chargedensity per phase into electrical energy for a given device are wellknown in the art.

Memory 114 may store power data and data pertaining to a responseassociated with sympatho-excitation of an effector, from system 116. Forinstance, memory 114 may store data pertaining to one or morephysiological parameters (which are further discussed below) detected byphysiological sensor 111, and/or the one or more corresponding aresponse associated with sympatho-excitation of an effector determinedvia physiological data processing module 115. In addition oralternatively, memory 114 may store power data and data pertaining tothe physiological parameters and/or responses associated withsympatho-excitation of an effector from external system 118 via theimplantable transceiver 110. For instance, memory 114 may store how muchcharge density per phase has been applied to the nerve, or how muchcharge density per phase the controller 101 and/or microprocessor 113estimates will be applied to the nerve by a set of signal parameters. Tothis end, the implantable transceiver 110 may form part of acommunication subsystem of the system 100, as is further discussedbelow.

Physiological data processing module 115 is configured to process one ormore physiological parameters detected by the physiological sensor 111,to determine one or more corresponding a response associated withsympatho-excitation of an effector. Physiological data processing module115 may be configured for reducing the size of the data pertaining tothe one or more physiological parameters for storing in memory 114and/or for transmitting to the external system via implantabletransceiver 110. Implantable transceiver 110 may comprise one or moreantenna(e). The implantable transceiver 100 may use any suitablesignaling process such as RF, wireless, infrared and so on, fortransmitting signals outside of the body, for instance to system 100 ofwhich the system 116 is one part.

Alternatively or additionally, physiological data processing module 115may be configured to process the one or more physiological parametersand/or process the determined responses in the subject to determine theevolution of a medical condition. In such case, the system 116, inparticular the implantable device 106, will include a capability ofcalibrating and tuning the signal parameters based on the one or morephysiological parameters of the subject and the determined evolution ofthe medical condition in the subject, as is further discussed below. Incalibrating and tuning the signal parameters, the system 116 mustensure, via the controller 101 and/or microprocessor 113 that the chargedensity per phase applied to the nerve by the calibrated signalparameters is below the predetermined threshold. To this end, controller101 and/or microprocessor 113 may store to memory the charge density perphase that has been applied, and the physiological sensor 111 may detectneural activity in the nerve to determine if the neural activity hasreturned to baseline activity. When the physiological sensor 111 detectsneural activity has returned to baseline activity, the controller 101and/or microprocessor 113 may reset the stored value of the chargedensity per phase applied.

The physiological data processing module 115 and the at least onephysiological sensor 111 may form a physiological sensor subsystem, alsoknown herein as a detector, either as part of the system 116, part ofthe implantable device 106, or external to the system 116.

Physiological sensor 111 comprises one or more sensors, each configuredto detect one of the one or more physiological parameters described indetail below. For example, the physiological sensor 110 is configuredfor one or more of: detecting the heart rate using a heart rate monitor,detecting electrical activity of the heart and/or heart rhythm using anelectrical sensor (e.g. an ECG recorder); detecting blood pressure (e.g.ventricular pressure) using a pressure sensor; or a combination thereof.Alternatively, the physiological sensor 111 comprises at least onerecording electrodes positioned on one of the at least one neuralinterfaces, to detect neural activity in the sympathetic chain.Preferably, in embodiments where the nerve is a cardiac-relatedsympathetic nerve, as shown in FIG. 7B, the at least one neuralinterface is positioned on the branch between the T2-T3 ganglia.

The physiological parameters determined by the physiological dataprocessing module 115 may be used to trigger the microprocessor 113 toapply a signal of the kinds described above to a nerve according to theinvention using the neural interfacing element (e.g. electrode 109).Upon receipt of the physiological parameter received from physiologicalsensor 111, the physiological data processor 115 may determine thephysiological parameter of the subject, and the evolution of the medicalcondition, by calculating in accordance with techniques known in theart.

The memory 114 may store physiological data pertaining to normal levelsof the one or more physiological parameters. The data may be specific tothe subject into which the system 116 is implanted, and gleaned fromvarious tests known in the art. Upon receipt of the physiologicalparameter received from physiological sensor 111, or else periodicallyor upon demand from physiological sensor 111, the physiological dataprocessor 115 may compare the physiological parameter determined by thesignal received from physiological sensor 111 with the data pertainingto a normal level of the physiological parameter stored in the memory114, and determine whether the received physiological parameter isindicative of the evolution of the medical condition in the subject.

The system 116 and/or implantable device 106 may be configured such thatif and when an insufficient or excessive level of a physiologicalparameter is determined by physiological data processor 115, thephysiological data processor 115 triggers apply of a signal to a nerveaccording to the invention by the neural interfacing element in themanner described elsewhere herein. For instance, if physiologicalparameter indicative of worsening of cardiac function, the physiologicaldata processor 115 may trigger apply of a signal which dampens theworsening cardiac dysfunction, as described elsewhere herein. Particularphysiological parameters relevant to the present invention are describedabove. When one or more of these physiological parameters are receivedby the physiological data processor 115, a signal may be applied to thenerve.

As an alternative to, or in addition to, the ability of the system 116and/or implantable device 106 to respond to physiological parameters ofthe subject, the microprocessor 113 may be triggered upon receipt of asignal generated by an operator (e.g. a physician or the subject inwhich the system 116 is implanted). To that end, the system 116 may bepart of a system 100 which comprises external system 118 and controller101, as is further described below.

System Including Implantable Device

With reference to FIG. 9 , the implantable device 106 of the inventionmay be part of a system 100 that includes a number of subsystems, forexample the system 116 and the external system 118. The external system118 may be used for powering, programming and providing operatorinteraction with the system 116 and/or the implantable device 106through human skin and underlying tissues. The implantable device 106applying a signal according to the present disclosure may be configuredeither externally or internally.

The external subsystem 118 may comprise, in addition to controller 101,one or more of: a powering unit 102, for wirelessly recharging thebattery of power source 112 used to power the implantable device 106; aprogramming unit 103 configured to communicate with the implantabletransceiver 110. The programming unit 103 and the implantabletransceiver 110 may form a communication subsystem. In some embodiments,powering unit 102 is housed together with programing unit 103. In otherembodiments, they can be housed in separate devices.

The external subsystem 118 may also comprise one or more of: powertransmission antenna 104; and data transmission antenna 105. Powertransmission antenna 104 may be configured for transmitting anelectromagnetic field at a low frequency (e.g., from 30 kHz to 10 MHz).Data transmission antenna 105 may be configured to transmit data forprogramming or reprogramming the implantable device 106, and may be usedin addition to the power transmission antenna 104 for transmitting anelectromagnetic field at a high frequency (e.g., from 1 MHz to 10 GHz).The temperature in the skin will not increase by more than 2 degreesCelsius above the surrounding tissue during the operation of the powertransmission antenna 104. The at least one antennae of the implantabletransceiver 110 may be configured to receive power from the externalelectromagnetic field generated by power transmission antenna 104, whichmay be used to charge the rechargeable battery of power source 112.

The power transmission antenna 104, data transmission antenna 105, andthe at least one antennae of implantable transceiver 110 have certaincharacteristics such a resonant frequency and a quality factor (Q). Oneimplementation of the antenna(e) is a coil of wire with or without aferrite core forming an inductor with a defined inductance. Thisinductor may be coupled with a resonating capacitor and a resistive lossto form the resonant circuit. The frequency is set to match that of theelectromagnetic field generated by the power transmission antenna 105. Asecond antenna of the at least one antennae of implantable transceiver110 can be used in system 116 for data reception and transmissionfrom/to the external system 118. If more than one antenna is used in thesystem 116, these antennae are rotated 30 degrees from one another toachieve a better degree of power transfer efficiency during slightmisalignment with the with power transmission antenna 104.

External system 118 may comprise one or more external body-wornphysiological sensors 121 (not shown) to detect one or morephysiological parameters. The signals may be transmitted to the system116 via the at least one antennae of implantable transceiver 110.Alternatively or additionally, the signals may be transmitted to theexternal system 116 and then to the system 116 via the at least oneantennae of implantable transceiver 110. As with physiologicalparameters detected by the implanted physiological sensor 111, thephysiological parameters detected by the external sensor 121 may beprocessed by the physiological data processing module 115 to determinethe one or more physiological parameters and/or stored in memory 114 tooperate the system 116 in a closed-loop fashion. The physiologicalparameters of the subject determined via signals received from theexternal sensor 121 may be used in addition to alternatively to thephysiological parameters determined via signals received from theimplanted physiological sensor 111.

The system 100 may include a safety protection feature that discontinuesthe electrical modulation of a nerve according to the invention in thefollowing exemplary events: abnormal operation of the system 116 (e.g.overvoltage); abnormal readout from an implanted physiological sensor111 (e.g. temperature increase of more than 2 degrees Celsius orexcessively high or low electrical impedance at the electrode-tissueinterface); abnormal readout from an external body-worn physiologicalsensor 121 (not shown); abnormal response to modulation detected by anoperator (e.g. a physician or the subject); or the charge density perphase applied to the nerve goes above the predetermined threshold. Thesafety precaution feature may be implemented via controller 101 andcommunicated to the system 116, or internally within the system 116.

The external system 118 may comprise an actuator 120 (not shown) which,upon being pressed by an operator (e.g. a physician or the subject),will apply a signal, via controller 101 and the respective communicationsubsystem, to trigger the microprocessor 113 of the system 116 to applya signal to the nerve by the neural interfacing element (e.g. electrode109).

System 100 of the invention, including the external system 118, but inparticular system 116, is preferably made from, or coated with, abiostable and biocompatible material. This means that the system 116 isboth protected from damage due to exposure to the body's tissues andalso minimizes the risk that the system 116 produces an unfavorablereaction by the host (which could ultimately lead to rejection). Thematerial used to make or coat the system 116 should ideally resist theformation of biofilms. Suitable materials include, but are not limitedto, poly(p-xylylene) polymers (known as Parylenes) andpolytetrafluoroethylene.

The implantable device 116 of the invention will generally weigh lessthan 50 g.

Application in Therapy

The invention involves treating and preventing conditions where thepathology is driven by exacerbated sympatho-excitation. For example,cardiac dysfunction, or metabolic disorders which involve impairedglucose control, such as T2D.

Treatment of the conditions described herein can be assessed in variousways, but typically involves determining an improvement in one or moreresponses of the subject. As used herein, an “improvement in a response”is taken to mean that, for any given response in a subject, animprovement is a change in a value indicative of that response (i.e. achange in a physiological parameter) in the subject towards the normalvalue or normal range for that value—i.e. towards the expected value ina healthy subject. That response is a response that is associated withthe reduction in sympatho-excitation in the effector.

As used herein, worsening of the effector function is taken to meanthat, for any given response in a subject, worsening is a change in avalue indicative of that response in the subject away from the normalvalue or normal range for that value—i.e. away from the expected valuein a healthy subject.

The invention may also involve detecting one or more physiologicalparameters of the subject, and hence responses associated withsympatho-excitation in the effector, which is indicative of effectorfunction. This may be done before, during and/or after modulation ofneural activity in the sympathetic nerve according to the invention. Thephysiological parameter may be organ-based or neuro-based, as describedfurther below.

For preventive use, a subject at risk of developing a condition wherethe pathology is driven by exacerbated sympatho-excitation may besubjected to signal application for x min at regular intervals, whereinx=≤3 min, ≤5 min, ≤10 min, ≤20 min, ≤30 min, ≤40 min, ≤50 min, ≤60 min,≤70 min, ≤80 min , ≤90 min, ≤120 min, or ≤240 min. The interval may beonce every day, once every 2 days, once every 3 days etc. The intervalmay be more than once a day, e.g. twice a day, three times a day etc.

A subject suitable for the invention may be any age, but will usually beat least 40, 45, 50, 55, 60, 65, 70, 75, 80 or 85 years of age.

As used herein, a physiological parameter is not affected by modulationof the neural activity of the sympathetic nerve according to theinvention if the parameter does not change (in response to thesympathetic nerve activity modulation) from the normal value or normalrange for that value of that parameter exhibited by the subject orsubject when no intervention has been performed i.e. it does not departfrom the baseline value for that parameter.

The skilled person will appreciate that the baseline for any neuralactivity or physiological parameter in an subject need not be a fixed orspecific value, but rather can fluctuate within a normal range or may bean average value with associated error and confidence intervals.Suitable methods for determining baseline values are well known to theskilled person.

As used herein, a physiological parameter is determined in a subjectwhen the value for that parameter exhibited by the subject at the timeof detection is determined. A detector (e.g. a physiological sensorsubsystem, a physiological data processing module, a physiologicalsensor, etc.) is any element able to make such a determination.

Thus, in certain embodiments, the invention further comprises a step ofdetermining one or more physiological parameters of the subject, whereinthe signal is applied only when the determined physiological parametermeets or exceeds a predetermined threshold value. In such embodimentswherein more than one physiological parameter of the subject isdetermined, the signal may be applied when any one of the determinedphysiological parameters meets or exceeds its threshold value,alternatively only when all of the determined physiological parametersmeet or exceed their threshold values. In certain embodiments whereinthe signal is applied by a system of the invention, the system furthercomprises at least one detector configured to determine the one or morephysiological parameters of the subject.

In certain embodiments, the physiological parameter is an actionpotential or pattern of action potentials in a nerve of the subject,wherein the action potential or pattern of action potentials isassociated with the condition that is to be treated. For example, thenerve is the sympathetic nerve according to the invention. In thisembodiment, the pattern of action potentials determined by the at leastone detector may be associated with a condition where the pathology isdriven by exacerbated sympatho-excitation, e.g. cardiac dysfunction.

It will be appreciated that any two physiological parameters may bedetermined in parallel embodiments, the controller is coupled detect thepattern of action potentials tolerance in the subject.

A predetermined threshold value for a physiological parameter is theminimum (or maximum) value for that parameter that must be exhibited bya subject or subject before the specified intervention is applied. Forany given parameter, the threshold value may be defined as a valueindicative of a pathological state or a disease state, or as a valueindicative of the onset of a pathological state or a disease state.Thus, depending on the predetermined threshold value, the invention canbe used as a treatment. Alternatively, the threshold value may bedefined as a value indicative of a physiological state of the subject(that the subject is, for example, asleep, post-prandial, orexercising). Appropriate values for any given physiological parameterwould be simply determined by the skilled person (for example, withreference to medical standards of practice).

Such a threshold value for a given physiological parameter is exceededif the value exhibited by the subject is beyond the threshold value—thatis, the exhibited value is a greater departure from the normal orhealthy value for that physiological parameter than the predeterminedthreshold value.

Treatment and Prevention of Cardiac Dysfunction

The invention involves treating or preventing cardiac dysfunction.

Increased sympathetic tone is associated with various cardiacconditions, e.g. heart failure, myocardial infarction, hypertension andcardiac arrhythmias. Hence in the embodiments where the effector is theheart, the invention is particularly useful for treating or preventingthese conditions.

In the embodiments where the effector is the foregut, the invention maylead to lowering of mesenteric vascular resistance, and so in suchembodiments the invention is particularly useful for treatinghypertension or heart failure.

The conditions associated with cardiac dysfunction are described furtherbelow.

Heart failure is a condition caused by the heart failing to pump enoughblood around the body to meet the demands of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease. Cardiacdecompensation is typically marked by dyspnea (difficulty breathing),venous engorgement and edema, and each decompensation event can causefurther long term deterioration of the heart function. Heart failurepatients have reduced autonomic balance, typically with a sympatheticoverdrive, which is associated with left ventricular dysfunction andincreased mortality. Heart failure, such as HFREF (heart failure withreduced ejection fraction) and HFpEF (heart failure with preservedejection faction), are particularly useful with the invention.

Myocardial infarction occurs when myocardial ischemia, a diminishedblood supply to the heart, exceeds a critical threshold and results inirreversible myocardial cell damage or death.

The invention is also useful in treating or preventing hypertension. Asubject who has hypertension has a blood pressure of 140/90 mmHg orhigher. In a normal subject, the ideal blood pressure is considered tobe between 90/60 mmHg and 120/80 mmHg. The invention may relate totreating or preventing cardiac arrhythmia, also called cardiacdysrhythmia (or simply irregular heart beat), which refers to a group ofconditions in which there is abnormal electrical activity in the heart.Some arrhythmias are life-threatening medical emergencies that canresult in cardiac arrest and sudden death. Other cause symptoms such asan abnormal awareness of heart beat. Others may not be associated withany symptoms at all but predispose toward potentially life-threateningstroke, embolus or cardiac arrest. Cardiac arrhythmia can be classifiedby rate (physiological, tachycardia or bradycardia), mechanism(automaticity, re-entry or fibrillation) or by site of origin(ventricular or supraventricular).

Preferably, the invention relates to treating or preventing ventriculararrhythmia, e.g. ventricular tachycardia (VT) and ventricularfibrillation (VF). Ventricular arrhythmias are characterized by adisruption in the normal excitation-contraction rhythm of heart. Inparticular, VT and VF are characterized by abnormally rapid,asynchronous contraction of the ventricles. As such, the heart is unableto adequately pump oxygenated blood to the systemic circulation. If nottreated immediately, ventricular arrhythmias can lead to additionaltissue damage or patient death. These potentially life threateningevents are characterized by, among other things, an increase intransient calcium currents and an elevation in diastolic calciumconcentration in cardiac tissue, lengthening of the cardiac actionpotential, a drop in blood pressure and ischemia (lack of adequate bloodflow to the heart). These changes can potentially affect the return ofspontaneous circulation, hemodynamics, refibrillation and resuscitationsuccess.

The invention is useful for subjects who are at risk of developingcardiac dysfunction. These subjects may be subjected to application ofthe signals described herein, thereby decreasing the arrhythmic burden.The cardiac testing strategies for subjects at risk of cardiacdysfunction are known in the art, e.g. heart rate variability (HRV),baroreflex sensitivity (BRS), heart rate turbulence (HRT), heart ratedeceleration capacity (HRDC) and T wave alternans (TWA). Deviation ofthese parameters from the baseline value range would be an indication ofthe subject being at risk of developing cardiac dysfunction.

Other indications include when the subject has a history of cardiacproblems or a history of myocardium injury. For example, the subject hasundergone heart procedures, e.g. heart surgery. The subject may have hada myocardial infarction. The subject may have emphysema or chronicobstructive pulmonary disease. The subject may have a history ofarrhythmia or is genetically pre-disposed to arrhythmia.

The invention can be used in combination with conventionalanti-arrhythmia therapies. For example, some arrhythmias, e.g. atrialfibrillation, cause blood clotting within the heart and increase risk ofembolus and stroke. Anticoagulant medications such as warfarin andheparin, and anti-platelet drugs such as aspirin can reduce the risk ofclotting. Thus, the invention can be used in combination withadministering an anticoagulant. The invention also provides ananticoagulant medicine for use in treating a subject, wherein thesubject has an implanted system of the invention in signaling contactwith a cardiac-related sympathetic nerve in the extracardiacintrathoracic neural circuit.

An organ-based biomarker useful for the invention may be any measurablephysiological parameter of the heart. For example, a physiologicalparameter may be one or more of the group consisting of: heart rate,heart rhythm, conduction and heart contractility (e.g. ventricularpressure, ventricular contractility, activation-recovery interval,effective refractory period, stroke volume, ejection fraction, enddiastolic fraction, stroke work, and arterial elastance). Theseparameters may indicate a chronotropic response, a dromotropic response,a lusitropic response and/or an inotropic response.

Chronotropic responses refer to changes in the heart rate and/or rhythm.These effects may be indicated using known techniques in the art, suchas by electrocardiography, e.g. using the RR-interval.

Dromotropic responses refer to changes to the conduction speed in theatrioventricular (AV) node. These effects may be indicated using knowntechniques in the art, such as by electrocardiography, e.g. using thePR-interval which would indicate the electrical spread across the atriato the AV-node.

Lusitropic responses refer to the changes in the rate of myocardialrelaxation. These effects may be indicated using known techniques in theart, such as by measuring the rate of pressure change in the ventricle(e.g. dP/dT).

Inotropic responses refer to the strength of contraction of heart muscle(i.e. myocardial contractility). These effects may be indicated usingknown techniques in the art, such as by measuring the rate of pressurechange in the ventricle (e.g. dP/dT).

Respiration parameters may also be useful. They can be derived from, forexample, a minute ventilation signal and a fluid index can be derivedfrom transthoracic impedance. For example decreasing thoracic impedancereflects increased fluid buildup in lungs, and indicates a progressionof heart failure. Respiration can significantly vary minute ventilation.The transthoracic impedance can be totaled or averaged to provide anindication of fluid buildup.

Heart Rate Variability (HRV) a technique useful for assess autonomicbalance. HRV relates to the regulation of the sinoatrial node, thenatural pacemaker of the heart by the sympathetic and parasympatheticbranches of the autonomic nervous system. An HRV assessment is based onthe assumption that the beat-to-beat fluctuations in the rhythm of theheart provide us with an indirect measure of heart health, as defined bythe degree of balance in sympathetic and parasympathetic nerve activity.

The invention may involve assessing the heart rate by methods known inthe art, for example, with a stethoscope or by feeling peripheralpulses. These methods cannot usually diagnose specific arrhythmias butcan give a general indication of the heart rate and whether it isregular or irregular. Not all of the electrical impulses of the heartproduce audible or palpable beats; in many cardiac arrhythmias, thepremature or abnormal beats do not produce an effective pumping actionand are experienced as “skipped” beats.

The invention may also involve assessing the heart rhythm. For example,the simplest specific diagnostic test for assessment of heart rhythm isthe electrocardiogram (abbreviated ECG or EKG). A Holter monitor is anEKG recorded over a 24-hour period, to detect arrhythmias that canhappen briefly and unpredictably throughout the day.

Other useful assessment techniques include using a cardiac eventrecorder; performing an electrophysiological (EP) study or performing anechocardiogram.

The invention may involve assessing a neuro-based biomarker. Hence, insome embodiments, the physiological parameter may be one or moreabnormal cardiac electrical signals from the subject indicative ofcardiac dysfunction. The abnormal cardiac electrical signals may bemeasured in a cardiac-related intrathoracic nerve or peripheral gangliaof the cardiac nervous system. The abnormal electric signals may be ameasurement of cardiac electric activity.

Example of assessing cardiac electrical signals include microneurographyor plasma noradrenaline concentration. Miconeurography involves usingfine electrodes to record ‘bursts’ of activity from multiple or singleafferent and efferent nerve axons [26,27]. The measurement of regionalplasma noradrenaline spillover is useful in providing information onsympathetic activity in individual organs. Following nervedepolarization, any remaining noradrenaline in the synapse, the‘spillover’, is washed out into the plasma and the plasma concentrationis therefore directly related to the rate of sympathetic neuronaldischarge [28,29,30].

For an example, in a subject having cardiac dysfunction, an improvement,and hence indicating a reduction in sympatho-excitation in the effector,may be indicated by a decrease in a chronotropic evoked response, adecrease in a dromotropic evoked response, a decrease in a lusitropicevoked response and/or a decrease in an inotropic evoked response. Animprovement in a measurable physiological parameters, and henceindicating a reduction in sympatho-excitation in the effector, may be adecrease in heart rate, conduction or heart contractility (e.g.ventricular pressure, ventricular contractility, activation-recoveryinterval, effective refractory period, stroke volume, ejection fraction,end diastolic fraction, stroke work, arterial elastance). The inventionmight not lead to a change in all of these parameters. Suitable methodsfor determining the value for any given parameter will be appreciated bythe skilled person.

In certain embodiments of the invention, treatment of the condition isindicated by an improvement in the profile of neural activity in thecardiac-related sympathetic nerve. That is, treatment of the conditionis indicated by the neural activity in the cardiac-related sympatheticnerve approaching the neural activity in a healthy subject.

Treatment of conditions associated with impaired glucose control

In embodiments where the effector is the foregut, the invention involvestreating subjects suffering from conditions associated with impairedglucose control. Conditions associated with impaired glucose controlinclude those conditions thought to cause the impairment (for exampleinsulin resistance, obesity, metabolic syndrome, Type 1 diabetes,Hepatitis C infection, acromegaly) and conditions resulting from theimpairment (for example obesity, sleep apnoea syndrome, dyslipidaemia,hypertension, Type 2 diabetes). It will be appreciated that someconditions can be both a cause of and caused by impaired glucosecontrol. Other conditions associated with impaired with glucose controlwould be appreciated by the skilled person. It will also be appreciatedthat these conditions may also be associated with insulin resistance.

The invention is of particular interest in relation to insulinresistance, prediabetes, and type 2 diabetes.

As used herein, “impaired glucose control” is taken to mean an inabilityto maintain blood glucose levels at a normal level (i.e. within normallimits for a healthy individual). As will be appreciated by the skilledperson, this will vary based on the type of subject and can bedetermined by a number of methods well known in the art, for example aglucose tolerance test (GTT). For example, in humans undergoing an oralglucose tolerance test, a glucose level at 2 hours of less than or equalto 7.8 mmol/L is considered normal. A glucose level at 2 hours of morethan 7.8 mmol/L is indicative of impaired glucose control.

As used herein, “insulin resistance” has its normal meaning in the arti.e. in subject or patient exhibiting insulin resistance, thephysiological response to insulin in the subject or patient isrefractory, such that a higher level of insulin is required in order tocontrol blood glucose levels, compared to the insulin level required ina healthy individual. Insulin sensitivity is used herein as thereciprocal to insulin resistance—that is, an increase in insulinsensitivity equates to a decrease in insulin resistance, and vice versa.Insulin resistance may be determined using any method known in the art,for example a GTT, a hyperinsulinaemic clamp or an insulin suppressiontest.

Treatment of the condition associated with impaired glucose control canbe assessed in various ways, but typically involves an improvement inone or more detected physiological parameters, and hence assessingresponses that are associated with the reduction in sympatho-excitationin the effector. For an example, in a subject having a conditionassociated with impaired glucose control (e.g. insulin resistance) animprovement in a measurable parameter (and hence a response associatedwith the reduction in sympatho-excitation in the effector) may(depending on which abnormal values a subject is exhibiting) be one ormore of: an increase in insulin sensitivity, a decrease in insulinresistance, a decrease in (fasting) plasma glucose concentration, areduction in total fat mass, a reduction in visceral fat mass, areduction in subcutaneous fat mass, a reduction in body mass index, areduction in obesity, a reduction in sympathetic tone, blood pressure, areduction in plasma and/or tissue catecholamines, reduction in urinarymetanephrines, a reduction in glycated haemoglobin (HbA1c), and/or areduction in circulating triglycerides. The invention might not lead toa change in all of these parameters.

In such embodiments, sympathetic tone is understood to be the neuralactivity in sympathetic nerves and/or associated sympatheticneurotransmitter measured in systemic or local tissue compartments inthe sympathetic nervous system. Suitable methods for determining thevalue for any given parameter will be appreciated by the skilled person.By way of example, an increase in heart rate and/or blood pressure for aperiod at least 24 hrs is typically indicative of an increasedsympathetic tone, as is aberrant heart rate variability, cardiac orrenal norepinephrine spillover, skin or muscle microneurography andplasma/urine norepinephrine. By way of further example, insulinsensitivity can be measured by the HOMA index or by a hyperinsulinemicclamp. By way of further example, total fat mass may be determined bybioimpedence. By way of further example, visceral fat can be indirectlydetermined by measuring abdominal perimeter. Further suitable methodsfor determining the value for any given parameter would be appreciatedby the skilled person.

In certain embodiments of the invention, treatment of the condition isindicated by an improvement in the profile of neural activity in theGSN. That is, treatment of the condition is indicated by the neuralactivity in the GSN approaching the neural activity in a healthyindividual.

Ideally, a subject displays an improvement in glucose tolerance asassessed by oral glucose tolerance test. Methods of the invention may beused to treat insulin resistance and T2D. The invention may also be usedto treat metabolic syndrome.

As used herein, a physiological parameter is not affected by inhibitionof GSN neural activity if the parameter does not change (in response toGSN activity inhibition) from the average value of that parameterexhibited by the subject or subject when no intervention has beenperformed i.e. it does not depart from the baseline value for thatparameter.

In certain embodiments of the method, the one or more detectedphysiological parameters useful with the invention are one or more ofthe group consisting of: sympathetic tone, blood pressure, plasmainsulin concentration, insulin sensitivity, plasma glucoseconcentration, glucose tolerance, total fat mass, visceral fat mass,plasma catecholamines (i.e. one or more of epinephrine, norepinephrine,metanephrine, normetanephrine and dopamine) content, tissuecatecholamines content urinary metanephrines content, plasma HbA1ccontent and a reduction in circulating triglyceride concentration.

By way of example, a typical HbA1c content in a healthy human subjectwould be between 20-42 mmol/mol (4-6% of total Hb). An HbA1c contentexceeding 42mmol/mol may be indicative of a diabetic state.

In certain embodiments, the detected physiological parameter is anaction potential or pattern of action potentials in a nerve of thesubject, wherein the action potential or pattern of action potentials isassociated with the condition associated with an impaired response toglucose that is to be treated. In certain such embodiments, the nerve isa sympathetic nerve.

In certain embodiments, the invention does not affect thecardiopulmonary regulation function of the GSN. In particularembodiments, the method does not affect one or more physiologicalparameters in the subject selected from the group consisting of: pO₂,pCO₂, blood pressure, oxygen demand and cardio-respiratory responses toexercise and altitude. Suitable methods for determining the value forany given parameter would be appreciated by the skilled person.

A subject of the invention may, in addition to having an implant,receive medicine for their condition. For instance, a subject having animplant according to the invention may receive a diabetes medicine(which will usually continue medication which was occurring beforereceiving the implant). Such medicines include, but are not limited to:metformin; sulfonylureas, such as glyburide, glipizide, or glimepiride;meglitinides, such as repaglinide or nateglinide; thiazolidinediones,such as rosiglitazone or pioglitazone; DPP-4 inhibitors, such assitagliptin, vildagliptin, saxagliptin or linagliptin; GLP-1 receptoragonists, such as exenatide or liraglutide; SGLT2 inhibitors, such ascanagliflozin or dapagliflozin. Thus the invention provides the use ofthese medicines in combination with a device/system of the invention.

General

The term “electrode” refers to a unipolar electrode unless otherwisespecified.

The term “comprising” encompasses “including” as well as “consisting”e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional e.g. X+Y.

The word “substantially” does not exclude “completely” e.g. acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

The term “about” and “around” in relation to a numerical value x isoptional and means, for example, x±10%.

Unless otherwise indicated each embodiment as described herein may becombined with another embodiment as described herein.

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1. A system for reversibly modulating the neural activity of asympathetic nerve, wherein the system comprises: at least two neuralinterfacing elements suitable for placement on or around the nerveadjacent to a ganglion, wherein the ganglion transmits sympatheticsignals between the ganglion and an effector; and at least one voltageor current source configured to generate at least one electrical signalto be applied to the nerve, via the at least two neural interfacingelements, to modulate the neural activity of the nerve to reducesympatho-excitation in the effector, wherein the at least two neuralinterfacing elements are configured such that the electrical signalincites action potentials in the nerve that propagate away from theeffector, towards the ganglion, wherein the charge density per phaseapplied to the nerve by the electrical signal is below a predeterminedthreshold, the predetermined threshold defined as the minimum chargedensity per phase required to produce a response associated withsympatho-excitation in the effector by modulating the neural activity ofthe sympathetic nerve.
 2. A method for reversibly modulating the neuralactivity of a sympathetic nerve, comprising: placing at least two neuralinterfacing elements on or around the nerve adjacent to a ganglion,wherein the ganglion transmits sympathetic signals between the ganglionand an effector; applying, by at least one voltage or current source, atleast one electrical signal to the nerve, via the at least two neuralinterfacing elements, to modulate the neural activity of the nerve toreduce sympatho-excitation in the effector, wherein the at least twoneural interfacing elements are configured such that the electricalsignal incites action potentials in the nerve which propagate away fromthe effector, towards the ganglion, wherein the charge density per phaseapplied to the nerve by the electrical signal is below a predeterminedthreshold, the predetermined threshold defined as the minimum chargedensity per phase required to produce a response associated withsympatho-excitation in the effector by modulating the neural activity ofthe sympathetic nerve.
 3. A method of reversibly modulating neuralactivity in a sympathetic nerve, comprising: (i) implanting in a subjecta system of claim 1; (ii) positioning the at least two neuralinterfacing elements of the system at the nerve adjacent to a ganglion;and optionally (iii) activating the system.